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Wang YX, Deng ZH, Li YY, Bai K, Ma J, Liu Y, Chen Q. Function of hematopoiesis and bone marrow niche in inflammation and non-hematopoietic diseases. LIFE MEDICINE 2025; 4:lnaf015. [PMID: 40376111 PMCID: PMC12076419 DOI: 10.1093/lifemedi/lnaf015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 03/24/2025] [Indexed: 05/18/2025]
Abstract
Hematopoiesis and the behavior of hematopoietic stem and progenitor cells (HSPCs) are regulated by the bone marrow niche. Here, we introduce the major niche cell types in bone marrow and their response to stress condition. We highlight the hematopoietic response and bone marrow niche adaptation to inflammatory condition and non-hematopoietic diseases, which are not systematically summarized. These emerging data suggest targeting hematopoiesis and bone marrow niche may provide novel therapeutic target to precisely control the progression of the diseases.
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Affiliation(s)
- Yu-xiang Wang
- Center for Cell Lineage Atlas, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
- University of Chinese Academy of Sciences, Beijing 101408, China
- China-New Zealand Belt and Road Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory for Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
| | - Zhao-hua Deng
- Center for Cell Lineage Atlas, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
- University of Chinese Academy of Sciences, Beijing 101408, China
- China-New Zealand Belt and Road Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory for Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
| | - Yu-yan Li
- Center for Cell Lineage Atlas, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
- University of Chinese Academy of Sciences, Beijing 101408, China
- China-New Zealand Belt and Road Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory for Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
| | - Ke Bai
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou 510006, China
| | - Jinjin Ma
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou 510006, China
- The Institute of Future Health, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, China
| | - Yang Liu
- The Innovation Centre of Ministry of Education for Development and Diseases, School of Medicine, South China University of Technology, Guangzhou 510006, China
| | - Qi Chen
- Center for Cell Lineage Atlas, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
- China-New Zealand Belt and Road Joint Laboratory on Biomedicine and Health, Guangdong Provincial Key Laboratory for Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
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IZU Y, ISHIKAWA H, SOETA S. Developmental process and homeostasis of whale long bones lacking medullary cavity using the radius of Antarctic minke whales, Balaenoptera bonaerensis. J Vet Med Sci 2025; 87:336-348. [PMID: 39938892 PMCID: PMC11964860 DOI: 10.1292/jvms.24-0430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 02/04/2025] [Indexed: 02/14/2025] Open
Abstract
Whales, Earth's largest mammals and live in water, form long bones without marrow cavities. Body size and mechanical stress impact the bone formation and homeostasis, yet the specific developmental processes remain unclear. Here, we demonstrate the histological changes in whale long bones from fetal to mature stages using the radius of Antarctic minke whales in comparison with domestic cats and cattle. Through intramembranous ossification and remodeling, long bones enlarge their diameters and marrow cavities, respectively. It has been demonstrated that relatively small animals, such as cats, develop the radially arranged "primary osteonal bone," whereas larger animals, including cattle, form "laminar bone" initiated by the formation of circumferentially arranged hypercalcified lines during intramembranous ossification. Here, we demonstrated that whales form laminar bones, transitioning from circumferential in the fetus to radial during postnatal growth, and thereafter cortical bones become compact. After maturation, bone remodeling primarily occurs in the lateral and medial regions of long bones, while the bone layers in the cranial-caudal region never undergo complete resorption. As a result, these layers remain as a wire-netting structure composed of thin bone layers, without forming an open medullary cavity. These data suggest that whales enlarge their long bones through laminar bone formation and form long bones without a marrow cavity by regulating bone resorption areas during the developmental process and in maintaining homeostasis.
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Affiliation(s)
- Yayoi IZU
- Laboratory of Comparative Cellular Biology, Nippon
Veterinary and Life Science University, Tokyo, Japan
- Department of Laboratory Animal Science, The Faculty of
Veterinary Medicine, Okayama University of Science, Ehime, Japan
| | - Hajime ISHIKAWA
- Japan Dolphin Center, Kagawa, Japan
- Institute of Cetacean Research, Tokyo, Japan
| | - Satoshi SOETA
- Department of Veterinary Anatomy, Nippon Veterinary and Life
Science University, Tokyo, Japan
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3
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Weldon KC, Longaker MT, Ambrosi TH. Harnessing the diversity and potential of endogenous skeletal stem cells for musculoskeletal tissue regeneration. Stem Cells 2025; 43:sxaf006. [PMID: 39945760 PMCID: PMC11892563 DOI: 10.1093/stmcls/sxaf006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 01/21/2025] [Indexed: 03/11/2025]
Abstract
In our aging society, the degeneration of the musculoskeletal system and adjacent tissues is a growing orthopedic concern. As bones age, they become more fragile, increasing the risk of fractures and injuries. Furthermore, tissues like cartilage accumulate damage, leading to widespread joint issues. Compounding this, the regenerative capacity of these tissues declines with age, exacerbating the consequences of fractures and cartilage deterioration. With rising demand for fracture and cartilage repair, bone-derived stem cells have attracted significant research interest. However, the therapeutic use of stem cells has produced inconsistent results, largely due to ongoing debates and uncertainties regarding the precise identity of the stem cells responsible for musculoskeletal growth, maintenance and repair. This review focuses on the potential to leverage endogenous skeletal stem cells (SSCs)-a well-defined population of stem cells with specific markers, reliable isolation techniques, and functional properties-in bone repair and cartilage regeneration. Understanding SSC behavior in response to injury, including their activation to a functional state, could provide insights into improving treatment outcomes. Techniques like microfracture surgery, which aim to stimulate SSC activity for cartilage repair, are of particular interest. Here, we explore the latest advances in how such interventions may modulate SSC function to enhance bone healing and cartilage regeneration.
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Affiliation(s)
- Kelly C Weldon
- Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA 95817, United States
- School of Medicine, University of California, Sacramento, CA 95817, United States
| | - Michael T Longaker
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, United States
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Thomas H Ambrosi
- Department of Orthopaedic Surgery, UC Davis Health, Sacramento, CA 95817, United States
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4
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Cong T, Morse KW, Sosa BR, Lane JM, Rodeo SA, Greenblatt MB. Skeletal Stem Cells: A Basis for Orthopaedic Pathology and Tissue Repair. J Bone Joint Surg Am 2025; 107:418-426. [PMID: 39693451 PMCID: PMC11839314 DOI: 10.2106/jbjs.24.00905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2024]
Abstract
➢ Skeletal stem cells (SSCs) continually replenish mature cell populations to support skeletal homeostasis.➢ SSCs repopulate by self-renewal, have multilineage potential, and are long-lived in vivo.➢ SSCs express specific combinations of cell surface markers that reflect their lineage identity.➢ SSCs adapt to their anatomic environment to support regional differences in skeletal behavior and pathology.
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Affiliation(s)
- Ting Cong
- Department of Orthopaedic Surgery, UPMC Sports Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
- Department of Orthopedic Surgery, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
| | - Kyle W Morse
- Hospital for Special Surgery, New York, NY
- Department of Orthopaedic Surgery, Weill Cornell Medicine, New York, NY
| | - Branden R Sosa
- Hospital for Special Surgery, New York, NY
- Department of Orthopaedic Surgery, Weill Cornell Medicine, New York, NY
| | - Joseph M Lane
- Hospital for Special Surgery, New York, NY
- Department of Orthopaedic Surgery, Weill Cornell Medicine, New York, NY
| | - Scott A Rodeo
- Hospital for Special Surgery, New York, NY
- Department of Orthopaedic Surgery, Weill Cornell Medicine, New York, NY
| | - Matthew B Greenblatt
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
- Research Division, Hospital for Special Surgery, New York, NY
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Kemna K, van der Burg M, Lankester A, Giera M. Hematopoietic stem cell metabolism within the bone marrow niche - insights and opportunities. Bioessays 2025; 47:e2400154. [PMID: 39506498 PMCID: PMC11755706 DOI: 10.1002/bies.202400154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 10/25/2024] [Accepted: 10/28/2024] [Indexed: 11/08/2024]
Abstract
Hematopoiesis unfolds within the bone marrow niche where hematopoietic stem cells (HSCs) play a central role in continually replenishing blood cells. The hypoxic bone marrow environment imparts peculiar metabolic characteristics to hematopoietic processes. Here, we discuss the internal metabolism of HSCs and describe external influences exerted on HSC metabolism by the bone marrow niche environment. Importantly, we suggest that the metabolic environment and metabolic cues are intertwined with HSC cell fate, and are crucial for hematopoietic processes. Metabolic dysregulation within the bone marrow niche during acute stress, inflammation, and chronic inflammatory conditions can lead to reduced HSC vitality. Additionally, we raise questions regarding metabolic stresses imposed on HSCs during implementation of stem cell protocols such as allo-SCT and gene therapy, and the potential ramifications. Enhancing our comprehension of metabolic influences on HSCs will expand our understanding of pathophysiology in the bone marrow and improve the application of stem cell therapies.
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Affiliation(s)
- Koen Kemna
- Department of Pediatrics, Laboratory for Pediatric ImmunologyWillem‐Alexander Children's Hospital, Leiden University Medical CenterLeidenThe Netherlands
| | - Mirjam van der Burg
- Department of Pediatrics, Laboratory for Pediatric ImmunologyWillem‐Alexander Children's Hospital, Leiden University Medical CenterLeidenThe Netherlands
| | - Arjan Lankester
- Department of Pediatrics, Laboratory for Pediatric ImmunologyWillem‐Alexander Children's Hospital, Leiden University Medical CenterLeidenThe Netherlands
| | - Martin Giera
- Center for Proteomics and MetabolomicsLeiden University Medical CenterLeidenThe Netherlands
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Cain TL, Derecka M, McKinney-Freeman S. The role of the haematopoietic stem cell niche in development and ageing. Nat Rev Mol Cell Biol 2025; 26:32-50. [PMID: 39256623 DOI: 10.1038/s41580-024-00770-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/23/2024] [Indexed: 09/12/2024]
Abstract
Blood production depends on rare haematopoietic stem cells (HSCs) and haematopoietic stem and progenitor cells (HSPCs) that ultimately take up residence in the bone marrow during development. HSPCs and HSCs are subject to extrinsic regulation by the bone marrow microenvironment, or niche. Studying the interactions between HSCs and their niche is critical for improving ex vivo culturing conditions and genetic manipulation of HSCs, which is pivotal for improving autologous HSC therapies and transplantations. Additionally, understanding how the complex molecular network in the bone marrow is altered during ageing is paramount for developing novel therapeutics for ageing-related haematopoietic disorders. HSCs are unique amongst stem and progenitor cell pools in that they engage with multiple physically distinct niches during their ontogeny. HSCs are specified from haemogenic endothelium in the aorta, migrate to the fetal liver and, ultimately, colonize their final niche in the bone marrow. Recent studies employing single-cell transcriptomics and microscopy have identified novel cellular interactions that govern HSC specification and engagement with their niches throughout ontogeny. New lineage-tracing models and microscopy tools have raised questions about the numbers of HSCs specified, as well as the functional consequences of HSCs interacting with each developmental niche. Advances have also been made in understanding how these niches are modified and perturbed during ageing, and the role of these altered interactions in haematopoietic diseases. In this Review, we discuss these new findings and highlight the questions that remain to be explored.
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Affiliation(s)
- Terri L Cain
- Department of Haematology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Marta Derecka
- Department of Haematology, St. Jude Children's Research Hospital, Memphis, TN, USA
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Xinyi Y, Vladimirovich RI, Beeraka NM, Satyavathi A, Kamble D, Nikolenko VN, Lakshmi AN, Basappa B, Reddy Y P, Fan R, Liu J. Emerging insights into epigenetics and hematopoietic stem cell trafficking in age-related hematological malignancies. Stem Cell Res Ther 2024; 15:401. [PMID: 39506818 PMCID: PMC11539620 DOI: 10.1186/s13287-024-04008-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 10/22/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Hematopoiesis within the bone marrow (BM) is a complex and tightly regulated process predominantly influenced by immune factors. Aging, diabetes, and obesity are significant contributors to BM niche damage, which can alter hematopoiesis and lead to the development of clonal hematopoiesis of intermediate potential (CHIP). Genetic/epigenetic alterations during aging could influence BM niche reorganization for hematopoiesis or clonal hematopoiesis. CHIP is driven by mutations in genes such as Tet2, Dnmt3a, Asxl1, and Jak2, which are associated with age-related hematological malignancies. OBJECTIVE This literature review aims to provide an updated exploration of the functional aspects of BM niche cells within the hematopoietic microenvironment in the context of age-related hematological malignancies. The review specifically focuses on how immunological stressors modulate different signaling pathways that impact hematopoiesis. METHODS An extensive review of recent studies was conducted, examining the roles of various BM niche cells in hematopoietic stem cell (HSC) trafficking and the development of age-related hematological malignancies. Emphasis was placed on understanding the influence of immunological stressors on these processes. RESULTS Recent findings reveal a significant microheterogeneity and temporal stochasticity of niche cells across the BM during hematopoiesis. These studies demonstrate that niche cells, including mesenchymal stem cells, osteoblasts, and endothelial cells, exhibit dynamic interactions with HSCs, significantly influenced by the BM microenvironment as the age increases. Immunosurveillance plays a crucial role in maintaining hematopoietic homeostasis, with alterations in immune signaling pathways contributing to the onset of hematological malignancies. Novel insights into the interaction between niche cells and HSCs under stress/aging conditions highlight the importance of niche plasticity and adaptability. CONCLUSION The involvement of age-induced genetic/epigenetic alterations in BM niche cells and immunological stressors in hematopoiesis is crucial for understanding the development of age-related hematological malignancies. This comprehensive review provides new insights into the complex interplay between niche cells and HSCs, emphasizing the potential for novel therapeutic approaches that target niche cell functionality and resilience to improve hematopoietic outcomes in the context of aging and metabolic disorders. NOVELTY STATEMENT This review introduces novel concepts regarding the plasticity and adaptability of BM niche cells in response to immunological stressors and epigenetics. It proposes that targeted therapeutic strategies aimed at enhancing niche cell resilience could mitigate the adverse effects of aging, diabetes, and obesity on hematopoiesis and clonal hematopoiesis. Additionally, the review suggests that understanding the precise temporal and spatial dynamics of niche-HSC interactions and epigenetics influence may lead to innovative treatments for age-related hematological malignancies.
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Affiliation(s)
- Yang Xinyi
- Department of Oncology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia
| | - Reshetov Igor Vladimirovich
- Department of Oncology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia
| | - Narasimha M Beeraka
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia.
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh, 515721, India.
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 W. Walnut Street, R4-168, Indianapolis, IN, 46202, USA.
- Department of Studies in Molecular Biology, Faculty of Science and Technology, University of Mysore, Mysore, Karnataka, 570006, India.
| | - Allaka Satyavathi
- Department of Chemistry, Faculty of science, Dr B R Ambedkar Open University, Wanaparthy, Telangana, 509103, India
| | - Dinisha Kamble
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 W. Walnut Street, R4-168, Indianapolis, IN, 46202, USA
| | - Vladimir N Nikolenko
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str, Moscow, 119991, Russia
| | - Allaka Naga Lakshmi
- Department of Computer Science, St Philomena's College (Autonomous), Bangalore - Mysore Rd, Bannimantap, Mysuru, Karnataka, 570015, India
| | - Basappa Basappa
- Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore, Karnataka, 570006, India
| | - Padmanabha Reddy Y
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh, 515721, India
| | - Ruitai Fan
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450000, China.
| | - Junqi Liu
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450000, China
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Ambrosi TH, Longaker MT. Charles "Chuck" K.F. Chan (1975-2024). Cell Stem Cell 2024; 31:1391-1392. [PMID: 39366359 DOI: 10.1016/j.stem.2024.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/06/2024] [Accepted: 09/06/2024] [Indexed: 10/06/2024]
Affiliation(s)
- Thomas H Ambrosi
- Department of Orthopaedic Surgery, University of California, Davis, Sacramento, CA 95817, USA.
| | - Michael T Longaker
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
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9
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Sánchez-Lanzas R, Jiménez-Pompa A, Ganuza M. The evolving hematopoietic niche during development. Front Mol Biosci 2024; 11:1488199. [PMID: 39417006 PMCID: PMC11480086 DOI: 10.3389/fmolb.2024.1488199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 09/20/2024] [Indexed: 10/19/2024] Open
Abstract
Mammalian hematopoietic stem cells (HSCs) emerge from the hemogenic endothelium in the major embryonic arteries. HSCs undergo a complex journey first migrating to the fetal liver (FL) and from there to the fetal bone marrow (FBM), where they mostly remain during adult life. In this process, a pool of adult HSCs is produced, which sustains lifelong hematopoiesis. Multiple cellular components support HSC maturation and expansion and modulate their response to environmental and developmental cues. While the adult HSC niche has been extensively studied over the last two decades, the niches present in the major embryonic arteries, FL, FBM and perinatal bone marrow (BM) are poorly described. Recent investigations highlight important differences among FL, FBM and adult BM niches and emphasize the important role that inflammation, microbiota and hormonal factors play regulating HSCs and their niches. We provide a review on our current understanding of these important cellular microenvironments across ontogeny. We mainly focused on mice, as the most widely used research model, and, when possible, include relevant insights from other vertebrates including birds, zebrafish, and human. Developing a comprehensive picture on these processes is critical to understand the earliest origins of childhood leukemia and to achieve multiple goals in regenerative medicine, such as mimicking HSC development in vitro to produce HSCs for broad transplantation purposes in leukemia, following chemotherapy, bone marrow failure, and in HSC-based gene therapy.
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Affiliation(s)
| | | | - Miguel Ganuza
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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10
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Sun B, Xu Y, Wang H, Wang F, Li Q, Chen Y, Wang Z. Autophagy Regulates Age-Related Jawbone Loss via LepR + Stromal Cells. J Dent Res 2024; 103:1028-1038. [PMID: 39185629 DOI: 10.1177/00220345241264810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024] Open
Abstract
Bone aging and decreased autophagic activity are related but poorly explored in the jawbone. This study aimed to characterize the aging jawbones and jawbone-derived stromal cells (JBSCs) and determine the role of autophagy in jawbone mass decline. We observed that the jawbones of older individuals and mice exhibited similar age-related bone loss. Furthermore, leptin receptor (LepR)-lineage cells served as the primary source for in vitro cultured and expanded JBSCs, referred to as LepR-Cre+/JBSCs. RNA-sequencing data from the jawbones and LepR-Cre+/JBSCs showed the upregulated expression of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway during aging. Through single-cell transcriptomics, we identified a decrease in the proportion of osteogenic lineage cells and the activation of the PI3K/AKT pathway in LepR-lineage cells in aging bone tissues. Reduced basal autophagic activity, diminished autophagic flux, and decreased osteogenesis occurred in the jawbones and LepR-Cre+/JBSCs from older mice (O-mice; O-JBSCs). Pharmacologic and constitutive autophagy activation alleviated the impaired osteogenesis in O-JBSCs. In addition, the suppression of mTOR-induced autophagy improved the aging phenotype of O-JBSCs. The activation of autophagy in LepR-Cre+/JBSCs using chemical autophagic activators reduced the alveolar bone resorption in O-mice. Therefore, our study demonstrated that ATG molecules and pathways are crucial in jawbone aging, providing novel approaches to understanding age-related jawbone loss.
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Affiliation(s)
- B Sun
- Department of Oral Implantology & Department of Oral and Maxillofacial Surgery, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Y Xu
- Department of Oral Implantology & Department of Oral and Maxillofacial Surgery, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - H Wang
- Department of Oral Implantology & Department of Oral and Maxillofacial Surgery, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - F Wang
- Department of Oral Implantology & Department of Oral and Maxillofacial Surgery, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Q Li
- Department of Oral Implantology & Department of Oral and Maxillofacial Surgery, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Y Chen
- Department of Oral Implantology & Department of Oral and Maxillofacial Surgery, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Z Wang
- Department of Oral Implantology & Department of Oral and Maxillofacial Surgery, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
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11
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Schleicher WE, Hoag B, De Dominici M, DeGregori J, Pietras EM. CHIP: a clonal odyssey of the bone marrow niche. J Clin Invest 2024; 134:e180068. [PMID: 39087468 PMCID: PMC11290965 DOI: 10.1172/jci180068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024] Open
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the selective expansion of hematopoietic stem and progenitor cells (HSPCs) carrying somatic mutations. While CHIP is typically asymptomatic, it has garnered substantial attention due to its association with the pathogenesis of multiple disease conditions, including cardiovascular disease (CVD) and hematological malignancies. In this Review, we will discuss seminal and recent studies that have advanced our understanding of mechanisms that drive selection for mutant HSPCs in the BM niche. Next, we will address recent studies evaluating potential relationships between the clonal dynamics of CHIP and hematopoietic development across the lifespan. Next, we will examine the roles of systemic factors that can influence hematopoietic stem cell (HSC) fitness, including inflammation, and exposures to cytotoxic agents in driving selection for CHIP clones. Furthermore, we will consider how - through their impact on the BM niche - lifestyle factors, including diet, exercise, and psychosocial stressors, might contribute to the process of somatic evolution in the BM that culminates in CHIP. Finally, we will review the role of old age as a major driver of selection in CHIP.
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Affiliation(s)
| | - Bridget Hoag
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Marco De Dominici
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - James DeGregori
- Division of Hematology, Department of Medicine, and
- Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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12
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Lim SU, Lee DW, Kim JH, Kang YJ, Kim IY, Oh IH. Chemical Coaxing of Mesenchymal Stromal Cells by Drug Repositioning for Nestin Induction. Int J Mol Sci 2024; 25:8006. [PMID: 39125577 PMCID: PMC11311338 DOI: 10.3390/ijms25158006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/16/2024] [Accepted: 07/17/2024] [Indexed: 08/12/2024] Open
Abstract
Mesenchymal stromal cells (MSCs) display heterogeneity in origin and functional role in tissue homeostasis. Subsets of MSCs derived from the neural crest express nestin and serve as niches in bone marrow, but the possibility of coaxing MSCs into nestin-expresing cells for enhanced supportive activity is unclear. In this study, as an approach to the chemical coaxing of MSC functions, we screened libraries of clinically approved chemicals to identify compounds capable of inducing nestin expression in MSCs. Out of 2000 clinical compounds, we chose vorinostat as a candidate to coax the MSCs into neural crest-like fates. When treated with vorinostat, MSCs exhibited a significant increase in the expression of genes involved in the pluripotency and epithelial-mesenchymal transition (EMT), as well as nestin and CD146, the markers for pericytes. In addition, these nestin-induced MSCs exhibited enhanced differentiation towards neuronal cells with the upregulation of neurogenic markers, including SRY-box transcription factor 2 (Sox2), SRY-box transcription factor 10 (Sox10) and microtubule associated protein 2 (Map2) in addition to nestin. Moreover, the coaxed MSCs exhibited enhanced supporting activity for hematopoietic progenitors without supporting leukemia cells. These results demonstrate the feasibility of the drug repositioning of MSCs to induce neural crest-like properties through the chemical coaxing of cell fates.
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Affiliation(s)
- Sun-Ung Lim
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, 222, Banpo-Daero, Seocho-Gu, Seoul 06591, Republic of Korea; (S.-U.L.); (D.-W.L.); (I.-Y.K.)
| | - Dae-Won Lee
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, 222, Banpo-Daero, Seocho-Gu, Seoul 06591, Republic of Korea; (S.-U.L.); (D.-W.L.); (I.-Y.K.)
| | - Jung-Ho Kim
- Regen Innopharm Inc., Seoul 06591, Republic of Korea; (J.-H.K.); (Y.-J.K.)
| | - Young-Ju Kang
- Regen Innopharm Inc., Seoul 06591, Republic of Korea; (J.-H.K.); (Y.-J.K.)
| | - In-Yong Kim
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, 222, Banpo-Daero, Seocho-Gu, Seoul 06591, Republic of Korea; (S.-U.L.); (D.-W.L.); (I.-Y.K.)
| | - Il-Hoan Oh
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University of Korea, 222, Banpo-Daero, Seocho-Gu, Seoul 06591, Republic of Korea; (S.-U.L.); (D.-W.L.); (I.-Y.K.)
- Regen Innopharm Inc., Seoul 06591, Republic of Korea; (J.-H.K.); (Y.-J.K.)
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13
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Pandey A, Hoover M, Singla M, Bedi Y, Storaci H, Goodman SB, Chan C, Bhutani N. TET1 Regulates Skeletal Stem-Cell Mediated Cartilage Regeneration. Arthritis Rheumatol 2024; 76:216-230. [PMID: 37610277 DOI: 10.1002/art.42678] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 08/02/2023] [Accepted: 08/15/2023] [Indexed: 08/24/2023]
Abstract
OBJECTIVE Adult skeletal stem cells (SSCs) that give rise to chondrocytes, osteocytes, and stromal cells as progeny have been shown to contribute to cartilage regeneration in osteoarthritis (OA). Understanding extrinsic and intrinsic regulators of SSC fate and function can therefore identify putative candidate factors to enhance cartilage regeneration. This study explores how the DNA hydroxymethylase Tet1 regulates SSC function in OA. METHODS We investigated the differences in the SSC lineage tree and differentiation potential in neonatal and adult Tet1+/+ and Tet1-/- mice with and without injury and upon OA induction and progression. Using RNA sequencing, the transcriptomic differences between SSCs and bone cartilage stroma progenitor cells (BCSPs) were identified in Tet1+/+ mice and Tet1-/- mice. RESULTS Loss of Tet1 skewed the SSC lineage tree by expanding the SSC pool and enhanced the chondrogenic potential of SSCs and BCSPs. Tet1 inhibition led to enhanced chondrogenesis in human SSCs and chondroprogenitors isolated from human cartilage. Importantly, TET1 inhibition in vivo in late stages of a mouse model of OA led to increased cartilage regeneration. Transcriptomic analyses of SSCs and BCSPs lacking Tet1 revealed pathway alterations in transforming growth factor β signaling, melatonin degradation, and cartilage development-associated genes. Lastly, we report that use of the hormone melatonin can dampen inflammation and improve cartilage health. CONCLUSION Although Tet1 is a broad epigenetic regulator, melatonin can mimic the inhibition ability of TET1 to enhance the chondrogenic ability of SSCs. Melatonin administration has the potential to be an attractive stem cell-based therapy for cartilage regeneration.
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14
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Schaller R, Moya A, Zhang G, Chaaban M, Paillaud R, Bartoszek EM, Schaefer DJ, Martin I, Kaempfen A, Scherberich A. Engineered phalangeal grafts for children with symbrachydactyly: A proof of concept. J Tissue Eng 2024; 15:20417314241257352. [PMID: 38872920 PMCID: PMC11171439 DOI: 10.1177/20417314241257352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 05/10/2024] [Indexed: 06/15/2024] Open
Abstract
Tissue engineering approaches hold great promise in the field of regenerative medicine, especially in the context of pediatric applications, where ideal grafts need to restore the function of the targeted tissue and consider growth. In the present study, we aimed to develop a protocol to engineer autologous phalangeal grafts of relevant size for children suffering from symbrachydactyly. This condition results in hands with short fingers and missing bones. A previously-described, developmentally-inspired strategy based on endochondral ossification (ECO)-the main pathway leading to bone and bone marrow development-and adipose derived-stromal cells (ASCs) as the source of chondroprogenitor was used. First, we demonstrated that pediatric ASCs associated with collagen sponges can generate hypertrophic cartilage tissues (HCTs) in vitro that remodel into bone tissue in vivo via ECO. Second, we developed and optimized an in vitro protocol to generate HCTs in the shape of small phalangeal bones (108-390 mm3) using freshly isolated adult cells from the stromal vascular fraction (SVF) of adipose tissue, associated with two commercially available large collagen scaffolds (Zimmer Plug® and Optimaix 3D®). We showed that after 12 weeks of in vivo implantation in an immunocompromised mouse model such upscaled grafts remodeled into bone organs (including bone marrow tissues) retaining the defined shape and size. Finally, we replicated similar outcome (albeit with a slight reduction in cartilage and bone formation) by using minimally expanded pediatric ASCs (3 × 106 cells per grafts) in the same in vitro and in vivo settings, thereby validating the compatibility of our pediatric phalanx engineering strategy with a clinically relevant scenario. Taken together, these results represent a proof of concept of an autologous approach to generate osteogenic phalangeal grafts of pertinent clinical size, using ASCs in children born with symbrachydactyly, despite a limited amount of tissue available from pediatric patients.
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Affiliation(s)
- Romain Schaller
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland
| | - Adrien Moya
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Gangyu Zhang
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Mansoor Chaaban
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Robert Paillaud
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Ewelina M Bartoszek
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Dirk J Schaefer
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland
| | - Ivan Martin
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Alexandre Kaempfen
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland
- Paediatric Orthopaedic, University Children’s Hospital Basel, Basel, Switzerland
| | - Arnaud Scherberich
- Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland
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15
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Cao Y, Bolam SM, Boss AL, Murray HC, Munro JT, Poulsen RC, Dalbeth N, Brooks AES, Matthews BG. Characterization of adult human skeletal cells in different tissues reveals a CD90 +CD34 + periosteal stem/progenitor population. Bone 2024; 178:116926. [PMID: 37793499 DOI: 10.1016/j.bone.2023.116926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/27/2023] [Accepted: 10/01/2023] [Indexed: 10/06/2023]
Abstract
The periosteum plays a crucial role in bone healing and is an important source of skeletal stem and progenitor cells. Recent studies in mice indicate that diverse populations of skeletal progenitors contribute to growth, homeostasis and healing. Information about the in vivo identity and diversity of skeletal stem and progenitor cells in different compartments of the adult human skeleton is limited. In this study, we compared non-hematopoietic populations in matched tissues from the femoral head and neck of 21 human participants using spectral flow cytometry of freshly isolated cells. High-dimensional clustering analysis indicated significant differences in marker distribution between periosteum, articular cartilage, endosteum and bone marrow populations, and identified populations that were highly enriched or unique to specific tissues. Periosteum-enriched markers included CD90 and CD34. Articular cartilage, which has very poor regenerative potential, showed enrichment of multiple markers, including the PDPN+CD73+CD164+CD146- population previously reported to represent human skeletal stem cells. We further characterized periosteal populations by combining CD90 with other strongly expressed markers. CD90+CD34+ cells sorted directly from periosteum showed significant colony-forming unit fibroblasts (CFU-F) enrichment, rapid expansion, and consistent multi-lineage differentiation of clonal populations in vitro. In situ, CD90+CD34+ cells include a perivascular population in the outer layer of the periosteum and non-perivascular cells closer to the bone surface. CD90+ cells are also highly enriched for CFU-F in bone marrow and endosteum, but not articular cartilage. In conclusion, our study indicates considerable diversity in the non-hematopoietic cell populations in different tissue compartments within the adult human skeleton, and suggests that periosteal progenitor cells reside within the CD90+CD34+ population.
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Affiliation(s)
- Ye Cao
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Scott M Bolam
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - Anna L Boss
- Department of Obstetrics and Gynaecology, University of Auckland, Auckland, New Zealand
| | - Helen C Murray
- Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand
| | - Jacob T Munro
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - Raewyn C Poulsen
- Department of Pharmacology, University of Auckland, Auckland, New Zealand
| | - Nicola Dalbeth
- Department of Medicine, University of Auckland, Auckland, New Zealand
| | - Anna E S Brooks
- School of Biological Sciences, University of Auckland, Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Brya G Matthews
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
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16
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Root SH, Matthews BG, Torreggiani E, Aguila HL, Kalajzic I. Hematopoietic and stromal DMP1-Cre labeled cells form a unique niche in the bone marrow. Sci Rep 2023; 13:22403. [PMID: 38104230 PMCID: PMC10725438 DOI: 10.1038/s41598-023-49713-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023] Open
Abstract
Skeletogenesis and hematopoiesis are interdependent. Niches form between cells of both lineages where microenvironmental cues support specific lineage commitment. Because of the complex topography of bone marrow (BM), the identity and function of cells within specialized niches has not been fully elucidated. Dentin Matrix Protein 1 (DMP1)-Cre mice have been utilized in bone studies as mature osteoblasts and osteocytes express DMP1. DMP1 has been identified in CXCL12+ cells and an undefined CD45+ population. We crossed DMP1-Cre with Ai9 reporter mice and analyzed the tdTomato+ (tdT+) population in BM and secondary hematopoietic organs. CD45+tdT+ express myeloid markers including CD11b and are established early in ontogeny. CD45+tdT+ cells phagocytose, respond to LPS and are radioresistant. Depletion of macrophages caused a significant decrease in tdT+CD11b+ myeloid populations. A subset of CD45+tdT+ cells may be erythroid island macrophages (EIM) which are depleted after G-CSF treatment. tdT+CXCL12+ cells are in direct contact with F4/80 macrophages, express RANKL and form a niche with B220+ B cells. A population of resident cells within the thymus are tdT+ and express myeloid markers and RANKL. In conclusion, in addition to targeting osteoblast/osteocytes, DMP1-Cre labels unique cell populations of macrophage and stromal cells within BM and thymus niches and expresses key microenvironmental factors.
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Affiliation(s)
- Sierra H Root
- Center for Regenerative Medicine and Skeletal Development, MC 3705, School of Dental Medicine, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA.
- Division of Pediatric Dentistry, MC1610, School of Dental Medicine, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA.
| | - Brya G Matthews
- Center for Regenerative Medicine and Skeletal Development, MC 3705, School of Dental Medicine, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Elena Torreggiani
- Center for Regenerative Medicine and Skeletal Development, MC 3705, School of Dental Medicine, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA
| | | | - Ivo Kalajzic
- Center for Regenerative Medicine and Skeletal Development, MC 3705, School of Dental Medicine, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA.
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17
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Matsuoka S, Facchini R, Luis TC, Carrelha J, Woll PS, Mizukami T, Wu B, Boukarabila H, Buono M, Norfo R, Arai F, Suda T, Mead AJ, Nerlov C, Jacobsen SEW. Loss of endothelial membrane KIT ligand affects systemic KIT ligand levels but not bone marrow hematopoietic stem cells. Blood 2023; 142:1622-1632. [PMID: 37562000 PMCID: PMC10733828 DOI: 10.1182/blood.2022019018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 08/12/2023] Open
Abstract
A critical regulatory role of hematopoietic stem cell (HSC) vascular niches in the bone marrow has been implicated to occur through endothelial niche cell expression of KIT ligand. However, endothelial-derived KIT ligand is expressed in both a soluble and membrane-bound form and not unique to bone marrow niches, and it is also systemically distributed through the circulatory system. Here, we confirm that upon deletion of both the soluble and membrane-bound forms of endothelial-derived KIT ligand, HSCs are reduced in mouse bone marrow. However, the deletion of endothelial-derived KIT ligand was also accompanied by reduced soluble KIT ligand levels in the blood, precluding any conclusion as to whether the reduction in HSC numbers reflects reduced endothelial expression of KIT ligand within HSC niches, elsewhere in the bone marrow, and/or systemic soluble KIT ligand produced by endothelial cells outside of the bone marrow. Notably, endothelial deletion, specifically of the membrane-bound form of KIT ligand, also reduced systemic levels of soluble KIT ligand, although with no effect on stem cell numbers, implicating an HSC regulatory role primarily of soluble rather than membrane KIT ligand expression in endothelial cells. In support of a role of systemic rather than local niche expression of soluble KIT ligand, HSCs were unaffected in KIT ligand deleted bones implanted into mice with normal systemic levels of soluble KIT ligand. Our findings highlight the need for more specific tools to unravel niche-specific roles of regulatory cues expressed in hematopoietic niche cells in the bone marrow.
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Affiliation(s)
- Sahoko Matsuoka
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Raffaella Facchini
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Tiago C. Luis
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College London, London, United Kingdom
| | - Joana Carrelha
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Petter S. Woll
- Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Takuo Mizukami
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Bishan Wu
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Hanane Boukarabila
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Mario Buono
- Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Ruggiero Norfo
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Fumio Arai
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshio Suda
- Cancer Science Institute, National University of Singapore, Singapore, Singapore
| | - Adam J. Mead
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Claus Nerlov
- Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Sten Eirik W. Jacobsen
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Department of Medicine Huddinge, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
- Medical Research Council Molecular Haematology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
- Karolinska University Hospital Huddinge, Stockholm, Sweden
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18
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Qing J, Guo Q, Lv L, Zhang X, Liu Y, Heng BC, Li Z, Zhang P, Zhou Y. Organoid Culture Development for Skeletal Systems. TISSUE ENGINEERING. PART B, REVIEWS 2023; 29:545-557. [PMID: 37183418 DOI: 10.1089/ten.teb.2023.0022] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
Organoids are widely considered to be ideal in vitro models that have been widely applied in many fields, including regenerative medicine, disease research and drug screening. It is distinguished from other three-dimensional in vitro culture model systems by self-organization and sustainability in long-term culture. The three core components of organoid culture are cells, exogenous factors, and culture matrix. Due to the complexity of bone tissue, and heterogeneity of osteogenic stem/progenitor cells, it is challenging to construct organoids for modeling skeletal systems. In this study, we examine current progress in the development of skeletal system organoid culture systems and analyze the current research status of skeletal stem cells, their microenvironmental factors, and various potential organoid culture matrix candidates to provide cues for future research trajectory in this field. Impact Statement The emergence of organoids has brought new opportunities for the development of many biomedical fields. The bone organoid field still has much room for exploration. This review discusses the characteristics distinguishing organoids from other three-dimensional model systems and examines current progress in the organoid production of skeletal systems. In addition, based on core elements of organoid cultures, three main problems that need to be solved in bone organoid generation are further analyzed. These include the heterogeneity of skeletal stem cells, their microenvironmental factors, and potential organoid culture matrix candidates. This information provides direction for the future research of bone organoids.
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Affiliation(s)
- Jia Qing
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Haidian District, Beijing, China
| | - Qian Guo
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Haidian District, Beijing, China
| | - Longwei Lv
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Haidian District, Beijing, China
| | - Xiao Zhang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Haidian District, Beijing, China
| | - Yunsong Liu
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Haidian District, Beijing, China
| | - Boon Chin Heng
- The Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Zheng Li
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Haidian District, Beijing, China
| | - Ping Zhang
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Haidian District, Beijing, China
| | - Yongsheng Zhou
- Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology, Haidian District, Beijing, China
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19
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Cao Y, Kalajzic I, Matthews BG. CD51 labels periosteal injury-responsive osteoprogenitors. Front Physiol 2023; 14:1231352. [PMID: 37731543 PMCID: PMC10507171 DOI: 10.3389/fphys.2023.1231352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 08/22/2023] [Indexed: 09/22/2023] Open
Abstract
The periosteum is a critical source of skeletal stem and progenitor cells (SSPCs) that form callus tissue in response to injury. There is yet to be a consensus on how to identify SSPCs in the adult periosteum. The aim of this study was to understand how potential murine periosteal SSPC populations behave in vivo and in response to injury. We evaluated the in vivo differentiation potential of Sca1-CD51+ and Sca1+CD51+ cells following transplantation. In vitro, the Sca1+CD51+ population appears to be more primitive multipotent cells, but after transplantation, Sca1-CD51+ cells showed superior engraftment, expansion, and differentiation into chondrocytes and osteoblasts. Despite representing a clear population with flow cytometry, we identified very few Sca1+CD51+ cells histologically. Using a periosteal scratch injury model, we successfully mimicked the endochondral-like healing process seen in unstable fractures, including the expansion and osteochondral differentiation of αSMA+ cells following injury. CD51+ cells were present in the cambium layer of resting periosteum and expanded following injury. Sca1+CD51- cells were mainly localized in the outer periosteal layer. We found that injury increased colony-forming unit fibroblast (CFU-F) formation in the periosteum and led to rapid expansion of CD90+ cells. Several other populations, including Sca1-CD51+ and CD34+ cells, were expanded by day 7. Mice with enhanced fracture healing due to elevated Notch signaling mediated by NICD1 overexpression showed significant expansion of CD51+ and CD34hi cells in the early stages of healing, suggesting these populations contribute to more rapid healing. In conclusion, we demonstrate that periosteal injury leads to the expansion of various SSPC populations, but further studies are required to confirm their lineage hierarchy in the adult skeletal system. Our data indicate that CD51+ skeletal progenitor cells are injury-responsive and show good engraftment and differentiation potential upon transplantation.
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Affiliation(s)
- Ye Cao
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
| | - Ivo Kalajzic
- Center for Regenerative Medicine and Skeletal Development, School of Dental Medicine, UConn Health, Farmington, CT, United States
| | - Brya G. Matthews
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand
- Center for Regenerative Medicine and Skeletal Development, School of Dental Medicine, UConn Health, Farmington, CT, United States
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20
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Bok S, Yallowitz AR, Sun J, McCormick J, Cung M, Hu L, Lalani S, Li Z, Sosa BR, Baumgartner T, Byrne P, Zhang T, Morse KW, Mohamed FF, Ge C, Franceschi RT, Cowling RT, Greenberg BH, Pisapia DJ, Imahiyerobo TA, Lakhani S, Ross ME, Hoffman CE, Debnath S, Greenblatt MB. A multi-stem cell basis for craniosynostosis and calvarial mineralization. Nature 2023; 621:804-812. [PMID: 37730988 PMCID: PMC10799660 DOI: 10.1038/s41586-023-06526-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 08/09/2023] [Indexed: 09/22/2023]
Abstract
Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC1 (CTSK+ CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2+ CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans2,3, solely in CTSK+ CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK+ CSCs and a corresponding expansion of DDR2+ CSCs, with DDR2+ CSC expansion being a direct maladaptive response to CTSK+ CSC depletion. DDR2+ CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2+ CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2+ CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK+ CSCs. Finally, the human counterparts of DDR2+ CSCs and CTSK+ CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency.
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Affiliation(s)
- Seoyeon Bok
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Alisha R Yallowitz
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Jun Sun
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Jason McCormick
- Flow Cytometry Core Facility, Weill Cornell Medicine, New York, NY, USA
| | - Michelle Cung
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Lingling Hu
- Department of Orthopedic Surgery, Hospital for Special Surgery, New York, NY, USA
| | - Sarfaraz Lalani
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Zan Li
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Branden R Sosa
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Tomas Baumgartner
- Flow Cytometry Core Facility, Weill Cornell Medicine, New York, NY, USA
| | - Paul Byrne
- Flow Cytometry Core Facility, Weill Cornell Medicine, New York, NY, USA
| | - Tuo Zhang
- Genomics Resources Core Facility, Weill Cornell Medicine, New York, NY, USA
| | - Kyle W Morse
- Department of Orthopedic Surgery, Hospital for Special Surgery, New York, NY, USA
| | - Fatma F Mohamed
- Department of Periodontics, Prevention and Geriatrics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Chunxi Ge
- Department of Periodontics, Prevention and Geriatrics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Renny T Franceschi
- Department of Periodontics, Prevention and Geriatrics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - Randy T Cowling
- Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, CA, USA
| | - Barry H Greenberg
- Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, CA, USA
| | - David J Pisapia
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Thomas A Imahiyerobo
- Division of Plastic Surgery, Department of Surgery, New York-Presbyterian Hospital and Columbia University Medical Center, New York, NY, USA
| | - Shenela Lakhani
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - M Elizabeth Ross
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Caitlin E Hoffman
- Department of Neurological Surgery, Weill Cornell Medicine and New York-Presbyterian Hospital, New York, NY, USA
| | - Shawon Debnath
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
| | - Matthew B Greenblatt
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
- Research Division, Hospital for Special Surgery, New York, NY, USA.
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21
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Zhang N, Barrell WB, Liu KJ. Identification of distinct subpopulations of Gli1-lineage cells in the mouse mandible. J Anat 2023; 243:90-99. [PMID: 36899483 PMCID: PMC10273353 DOI: 10.1111/joa.13858] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/22/2023] [Accepted: 02/23/2023] [Indexed: 03/12/2023] Open
Abstract
The Hedgehog pathway gene Gli1 has been proposed to mark a subpopulation of skeletal stem cells (SSCs) in craniofacial bone. Skeletal stem cells (SSCs) are multi-potent cells crucial for the development and homeostasis of bone. Recent studies on long bones have suggested that skeletal stem cells in endochondral or intramembranous ossification sites have different differentiation capacities. However, this has not been well-defined in neural crest derived bones. Generally, the long bones are derived from mesoderm and follow an endochondral ossification model, while most of the cranial bones are neural crest (NC) in origin and follow an intramembranous ossification model. The mandible is unique: It is derived from the neural crest lineage but makes use of both modes of ossification. Early in fetal development, the mandibular body is generated by intramembranous ossification with subsequent endochondral ossification forming the condyle. The identities and properties for SSCs in these two sites remain unknown. Here, we use genetic lineage tracing in mouse to identify cells expressing the Hedgehog responsive gene Gli1, which is thought to mark the tissue resident SSCs. We track the Gli1+ cells, comparing cells within the perichondrium to those in the periosteum covering the mandibular body. In juvenile mice, these have distinct differentiation and proliferative potential. We also assess the presence of Sox10+ cells, thought to mark neural crest stem cells, but find no substantial population associated with the mandibular skeleton, suggesting that Sox10+ cells have limited contribution to maintaining postnatal mandibular bone. All together, our study indicates that the Gli1+ cells display distinct and limited differentiation capacity dependent on their regional associations.
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Affiliation(s)
- Nian Zhang
- Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial SciencesKing's College LondonLondonUK
- State Key Laboratory of Oral Disease, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral DiseasesWest China Hospital of Stomatogy, Sichuan UniversityChengduChina
| | - William B. Barrell
- Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial SciencesKing's College LondonLondonUK
| | - Karen J. Liu
- Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial SciencesKing's College LondonLondonUK
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22
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Hagedorn EJ, Perlin JR, Freeman RJ, Wattrus SJ, Han T, Mao C, Kim JW, Fernández-Maestre I, Daily ML, D'Amato C, Fairchild MJ, Riquelme R, Li B, Ragoonanan DAVE, Enkhbayar K, Henault EL, Wang HG, Redfield SE, Collins SH, Lichtig A, Yang S, Zhou Y, Kunar B, Gomez-Salinero JM, Dinh TT, Pan J, Holler K, Feldman HA, Butcher EC, van Oudenaarden A, Rafii S, Junker JP, Zon LI. Transcription factor induction of vascular blood stem cell niches in vivo. Dev Cell 2023; 58:1037-1051.e4. [PMID: 37119815 PMCID: PMC10330626 DOI: 10.1016/j.devcel.2023.04.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/08/2023] [Accepted: 04/07/2023] [Indexed: 05/01/2023]
Abstract
The hematopoietic niche is a supportive microenvironment composed of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses in zebrafish, we define a conserved gene expression signature and cis-regulatory landscape that are unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code that involves members of the Ets, Sox, and nuclear hormone receptor families and is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance, and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.
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Affiliation(s)
- Elliott J Hagedorn
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA; Section of Hematology and Medical Oncology and Center for Regenerative Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
| | - Julie R Perlin
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Rebecca J Freeman
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Samuel J Wattrus
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Tianxiao Han
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Clara Mao
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Ji Wook Kim
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Inés Fernández-Maestre
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Madeleine L Daily
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Christopher D'Amato
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Michael J Fairchild
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Raquel Riquelme
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Brian Li
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Dana A V E Ragoonanan
- Section of Hematology and Medical Oncology and Center for Regenerative Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
| | - Khaliun Enkhbayar
- Section of Hematology and Medical Oncology and Center for Regenerative Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
| | - Emily L Henault
- Section of Hematology and Medical Oncology and Center for Regenerative Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
| | - Helen G Wang
- Section of Hematology and Medical Oncology and Center for Regenerative Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
| | - Shelby E Redfield
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Samantha H Collins
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Asher Lichtig
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Song Yang
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Yi Zhou
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA
| | - Balvir Kunar
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Jesus Maria Gomez-Salinero
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Thanh T Dinh
- Veterans Affairs Palo Alto Health Care System, The Palo Alto Veterans Institute for Research and the Department of Pathology, Stanford University, Stanford, CA, USA
| | - Junliang Pan
- Veterans Affairs Palo Alto Health Care System, The Palo Alto Veterans Institute for Research and the Department of Pathology, Stanford University, Stanford, CA, USA
| | - Karoline Holler
- Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine, Berlin, Germany
| | - Henry A Feldman
- Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA
| | - Eugene C Butcher
- Veterans Affairs Palo Alto Health Care System, The Palo Alto Veterans Institute for Research and the Department of Pathology, Stanford University, Stanford, CA, USA
| | - Alexander van Oudenaarden
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands
| | - Shahin Rafii
- Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - J Philipp Junker
- Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine, Berlin, Germany
| | - Leonard I Zon
- Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Harvard Stem Cell Institute, Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA, USA.
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23
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Lee DW, Shin S, Kim JH, Lee C, Kim IY, Oh IH. Antisense Oligonucleotides against Let-7 Enhance the Therapeutic Potential of Mesenchymal Stromal Cells. Int J Mol Sci 2023; 24:ijms24108639. [PMID: 37239986 DOI: 10.3390/ijms24108639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/30/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Let-7 miRNAs have pleiotropic cellular functions in cell proliferation, migration, and regenerative processes. Here, we investigate whether the inhibition of let-7 miRNAs with antisense oligonucleotides (ASOs) can be a transient and safe strategy enhancing the therapeutic potential of mesenchymal stromal cells (MSCs) to overcome their limitations in cell therapeutic trials. We first identified major subfamilies of let-7 miRNAs preferentially expressed in MSCs, and efficient ASO combinations against these selected subfamilies that mimic the effects of LIN28 activation. When let-7 miRNAs were inhibited with an ASO combination (anti-let7-ASOs), MSCs exhibited higher proliferation with delayed senescence during the passaging into a culture. They also exhibited increased migration and enhanced osteogenic differentiation potential. However, these changes in MSCs were not accompanied by cell-fate changes into pericytes or the additional acquisition of stemness, but instead occurred as functional changes accompanied by changes in proteomics. Interestingly, MSCs with let-7 inhibition exhibited metabolic reprogramming characterized by an enhanced glycolytic pathway, decreased reactive oxygen species, and lower transmembrane potential in mitochondria. Moreover, let-7-inhibited MSCs promoted the self-renewal of neighboring hematopoietic progenitor cells, and enhanced capillary formation in endothelial cells. These findings together show that our optimized ASO combination efficiently reprograms the MSC functional state, allowing for more efficient MSC cell therapy.
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Affiliation(s)
- Dae-Won Lee
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University, Seoul 06591, Republic of Korea
| | - Sungho Shin
- Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
- KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jeong-Ho Kim
- Regen Innopharm Inc., Seoul 06591, Republic of Korea
| | - Cheolju Lee
- Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea
| | - In Yong Kim
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University, Seoul 06591, Republic of Korea
| | - Il-Hoan Oh
- Catholic High-Performance Cell Therapy Center & Department of Medical Life Science, College of Medicine, The Catholic University, Seoul 06591, Republic of Korea
- Regen Innopharm Inc., Seoul 06591, Republic of Korea
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24
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O’Neill HC, Lim HK. Skeletal stem/progenitor cells provide the niche for extramedullary hematopoiesis in spleen. Front Physiol 2023; 14:1148414. [PMID: 37007998 PMCID: PMC10063897 DOI: 10.3389/fphys.2023.1148414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/10/2023] [Indexed: 03/19/2023] Open
Abstract
In bone marrow, the niche which supports hematopoiesis and nurtures hematopoietic stem cells (HSCs) contains perivascular reticular cells representing a subset of skeletal stem/progenitor cells (SSPCs). These stromal cells which provide the niche are lost or become inadequate during stress, disease or ageing, such that HSCs leave bone marrow and enter spleen and other peripheral sites to initiate extramedullary hematopoiesis and particularly myelopoiesis. Spleen also maintains niches for HSCs under steady-state conditions, evident since neonatal and adult spleen contain HSCs in low number and provide low-level hematopoiesis. In spleen, HSCs are found in the sinusoidal-rich red pulp region also in the vicinity of perivascular reticular cells. These cells resemble to some extent the known stromal elements reflecting HSC niches in bone marrow, and are investigated here for their characteristics as a subset of SSPCs. The isolation of spleen stromal subsets and the generation of cell lines which support HSCs and myelopoiesis in vitro has led to the identification of perivascular reticular cells which are unique to spleen. Analysis of gene and marker expression, as well as differentiative potential, identifies an osteoprogenitor cell type, reflective of one of several subsets of SSPCs described previously in bone, bone marrow and adipose tissue. The combined information supports a model for HSC niches in spleen involving perivascular reticular cells as SSPCs having osteogenic, stroma-forming capacity. These associate with sinusoids in red pulp to form niches for HSCs and to support the differentiation of hematopoietic progenitors during extramedullary hematopoiesis.
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25
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Koerber RM, Schneider RK, Pritchard JE, Teichmann LL, Schumacher U, Brossart P, Gütgemann I. Nestin expression in osteocytes following myeloablation and during bone marrow metastasis. Br J Haematol 2023; 200:643-651. [PMID: 36382360 DOI: 10.1111/bjh.18563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/19/2022] [Accepted: 11/02/2022] [Indexed: 11/18/2022]
Abstract
Nestin is an intermediate filament protein, which was originally detected in neuroepithelial stem cells. Besides its use as a phenotypic marker of mesenchymal stem cells in the hematopoeitic stem cell niche, the functional interpretation of nestin+ cells remains elusive. We investigated the cellular expression of nestin in bone marrow trephine biopsies of MPN patients, following myeloablation at a stage of hypocellularity during early regeneration. Here, nestin is highly expressed in mature osteocytes, arteriolar endothelial and perivascular cells and small capillaries within the bone marrow space, but not in sinusoid lining cells. This is in stark contrast to nestin expression pattern in myeloproliferative neoplasms that show hypercellularity due to oncogenic driver mutations. Here, nestin is expressed exclusively in endothelial cells of arterioles, but not in osteocytes or small capillaries. Thus, the pattern of nestin expression following myeloablation inversely correlates with cellularity in the bone marrow. This nestin expression pattern is mimicking early postnatal transcriptional programming during bone marrow development. We show that nestin expression in osteocytes occurs across different species following transplant and also in bone marrow metastasis.
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Affiliation(s)
- Ruth-Miriam Koerber
- Department of Medicine III, University Hospital Bonn, Bonn, Germany.,Mildred Scheel School of Oncology, Medical Faculty, University Hospital Bonn, Bonn, Germany
| | - Rebekka K Schneider
- Department of Cell Biology, Institute for Biomedical Engineering, Aachen, Germany
| | | | - Lino L Teichmann
- Department of Medicine III, University Hospital Bonn, Bonn, Germany
| | - Udo Schumacher
- Institute of Anatomy and Experimental Morphology, University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Peter Brossart
- Department of Medicine III, University Hospital Bonn, Bonn, Germany
| | - Ines Gütgemann
- Institute of Pathology, University Hospital Bonn, Bonn, Germany
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26
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Solidum JGN, Jeong Y, Heralde F, Park D. Differential regulation of skeletal stem/progenitor cells in distinct skeletal compartments. Front Physiol 2023; 14:1137063. [PMID: 36926193 PMCID: PMC10013690 DOI: 10.3389/fphys.2023.1137063] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 02/16/2023] [Indexed: 03/06/2023] Open
Abstract
Skeletal stem/progenitor cells (SSPCs), characterized by self-renewal and multipotency, are essential for skeletal development, bone remodeling, and bone repair. These cells have traditionally been known to reside within the bone marrow, but recent studies have identified the presence of distinct SSPC populations in other skeletal compartments such as the growth plate, periosteum, and calvarial sutures. Differences in the cellular and matrix environment of distinct SSPC populations are believed to regulate their stemness and to direct their roles at different stages of development, homeostasis, and regeneration; differences in embryonic origin and adjacent tissue structures also affect SSPC regulation. As these SSPC niches are dynamic and highly specialized, changes under stress conditions and with aging can alter the cellular composition and molecular mechanisms in place, contributing to the dysregulation of local SSPCs and their activity in bone regeneration. Therefore, a better understanding of the different regulatory mechanisms for the distinct SSPCs in each skeletal compartment, and in different conditions, could provide answers to the existing knowledge gap and the impetus for realizing their potential in this biological and medical space. Here, we summarize the current scientific advances made in the study of the differential regulation pathways for distinct SSPCs in different bone compartments. We also discuss the physical, biological, and molecular factors that affect each skeletal compartment niche. Lastly, we look into how aging influences the regenerative capacity of SSPCs. Understanding these regulatory differences can open new avenues for the discovery of novel treatment approaches for calvarial or long bone repair.
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Affiliation(s)
- Jea Giezl Niedo Solidum
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Manila, Philippines
- Department of Molecular and Human Genetics, Houston, TX, United States
| | - Youngjae Jeong
- Department of Molecular and Human Genetics, Houston, TX, United States
| | - Francisco Heralde
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila, Manila, Philippines
| | - Dongsu Park
- Department of Molecular and Human Genetics, Houston, TX, United States
- Center for Skeletal Biology, Baylor College of Medicine, Houston, TX, United States
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27
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Denervation during mandibular distraction osteogenesis results in impaired bone formation. Sci Rep 2023; 13:2097. [PMID: 36747028 PMCID: PMC9902545 DOI: 10.1038/s41598-023-27921-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 01/10/2023] [Indexed: 02/08/2023] Open
Abstract
Mandibular distraction osteogenesis (DO) is mediated by skeletal stem cells (SSCs) in mice, which enact bone regeneration via neural crest re-activation. As peripheral nerves are essential to progenitor function during development and in response to injury, we questioned if denervation impairs mandibular DO. C57Bl6 mice were divided into two groups: DO with a segmental defect in the inferior alveolar nerve (IAN) at the time of mandibular osteotomy ("DO Den") and DO with IAN intact ("DO Inn"). DO Den demonstrated significantly reduced histological and radiological osteogenesis relative to DO Inn. Denervation preceding DO results in reduced SSC amplification and osteogenic potential in mice. Single cell RNA sequencing analysis revealed that there was a predominance of innervated SSCs in clusters dominated by pathways related to bone formation. A rare human patient specimen was also analyzed and suggested that histological, radiological, and transcriptional alterations seen in mouse DO may be conserved in the setting of denervated human mandible distraction. Fibromodulin (FMOD) transcriptional and protein expression were reduced in denervated relative to innervated mouse and human mandible regenerate. Finally, when exogenous FMOD was added to DO-Den and DO-Inn SSCs undergoing in vitro osteogenic differentiation, the osteogenic potential of DO-Den SSCs was increased in comparison to control untreated DO-Den SSCs, modeling the superior osteogenic potential of DO-Inn SSCs.
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28
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Hyaluronic acid hydrogels support to generate integrated bone formation through endochondral ossification in vivo using mesenchymal stem cells. PLoS One 2023; 18:e0281345. [PMID: 36730328 PMCID: PMC9894498 DOI: 10.1371/journal.pone.0281345] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 01/20/2023] [Indexed: 02/03/2023] Open
Abstract
Engineered cartilage tissue from differentiated mesenchymal stem cells (MSCs) can generate bone in vivo through endochondral ossification (ECO). This ECO-mediated approach has the potential to circumvent the severe problems associated with conventional MSC-based bone tissue engineering techniques that lack mechanisms to induce angiogenesis. Hyaluronic acid (HA) is a key component in the cartilage extracellular matrix. However, the ECO-supporting properties of HA remain largely unclear. This study aimed to compare the ability of HA and collagen hydrogels to support in vitro differentiation of MSC-based hypertrophic cartilage tissues and to promote endochondral bone formation in vivo. Following the chondrogenic and hypertrophic differentiation in vitro, both HA and collagen constructs accumulated sulfated glycosaminoglycan (sGAG) and type 1, type II, and type X collagen. However, HA hydrogels exhibited a more uniform distribution of sGAG, type 1 collagen, type X collagen, and osteocalcin proteins; in addition, the cells embedded in the hydrogels had more rounded cell morphologies than those in the collagen constructs. At week 5 of in vitro culture, two to three constructs were implanted into a subcutaneous pocket in nude mice and harvested after 4 and 8 weeks. Both HA and collagen constructs promoted endochondral bone formation with vascularization and bone marrow development; however, the HA constructs fused to form integrated bone tissues and the bone marrow developed along the space between the two adhered grafts in all implanted pockets (n = 5). In the collagen constructs, the integration was observed in 40% of the pockets (n = 5). Microcomputer CT analysis revealed that the bone volume of HA constructs was larger than that of collagen constructs. In conclusion, compared to collagen hydrogels, HA hydrogels had superior potential to generate integrated bone with vascularization and bone marrow development. This study provides valuable insights for applying ECO-mediated bone tissue engineering approaches for the repair of critical-sized bone defects.
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29
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Resource: A Cellular Developmental Taxonomy of the Bone Marrow Mesenchymal Stem Cell Population in Mice. Hemasphere 2023; 7:e823. [PMID: 36741354 PMCID: PMC9891453 DOI: 10.1097/hs9.0000000000000823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 11/29/2022] [Indexed: 02/03/2023] Open
Abstract
Mesenchymal stem cells (MSCs) play pivotal roles in tissue (re)generation. In the murine bone marrow, they are thought to reside within the Sca-1+ CD51+ bone marrow stromal cell population. Here, using scRNAseq, we aimed to delineate the cellularheterogeneity of this MSC-enriched population throughout development. At the fetal stage, the MSC population is relatively homogeneous with subsets predicted to contain stem/progenitor cells, based on transcriptional modeling and marker expression. These subsets decline in relative size throughout life, with postnatal emergence of specialized clusters, including hematopoietic stem/progenitor cell (HSPC) niches. In fetal development, these stromal HSPC niches are lacking, but subsets of endothelial cells express HSPC factors, suggesting that they may provide initial niches for emerging hematopoiesis. This cellular taxonomy of the MSC population upon development is anticipated to provide a resource aiding the prospective identification of cellular subsets and molecular mechanisms driving bone marrow (re)generation.
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30
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Liu Y, Ilinski A, Gerstenfeld LC, Bragdon B. Prx1 cell subpopulations identified in various tissues with diverse quiescence and activation ability following fracture and BMP2 stimulation. Front Physiol 2023; 14:1106474. [PMID: 36793419 PMCID: PMC9922707 DOI: 10.3389/fphys.2023.1106474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 01/18/2023] [Indexed: 01/31/2023] Open
Abstract
The expression of Prx1 has been used as a marker to define the skeletal stem cells (SSCs) populations found within the bone marrow and periosteum that contribute to bone regeneration. However, Prx1 expressing SSCs (Prx1-SSCs) are not restricted to the bone compartments, but are also located within the muscle and able to contribute to ectopic bone formation. Little is known however, about the mechanism(s) regulating Prx1-SSCs that reside in muscle and how they participate in bone regeneration. This study compared both the intrinsic and extrinsic factors of the periosteum and muscle derived Prx1-SSCs and analyzed their regulatory mechanisms of activation, proliferation, and skeletal differentiation. There was considerable transcriptomic heterogeneity in the Prx1-SSCs found in muscle or the periosteum however in vitro cells from both tissues showed tri-lineage (adipose, cartilage and bone) differentiation. At homeostasis, periosteal-derived Prx1 cells were proliferative and low levels of BMP2 were able to promote their differentiation, while the muscle-derived Prx1 cells were quiescent and refractory to comparable levels of BMP2 that promoted periosteal cell differentiation. The transplantation of Prx1-SCC from muscle and periosteum into either the same site from which they were isolated, or their reciprocal sites showed that periosteal cell transplanted onto the surface of bone tissues differentiated into bone and cartilage cells but was incapable of similar differentiation when transplanted into muscle. Prx1-SSCs from the muscle showed no ability to differentiate at either site of transplantation. Both fracture and ten times the BMP2 dose was needed to promote muscle-derived cells to rapidly enter the cell cycle as well as undergo skeletal cell differentiation. This study elucidates the diversity of the Prx1-SSC population showing that cells within different tissue sites are intrinsically different. While muscle tissue must have factors that promote Prx1-SSC to remain quiescent, either bone injury or high levels of BMP2 can activate these cells to both proliferate and undergo skeletal cell differentiation. Finally, these studies raise the possibility that muscle SSCs are potential target for skeletal repair and bone diseases.
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Affiliation(s)
| | | | | | - Beth Bragdon
- Department of Orthopaedic Surgery, Boston University School of Medicine, Boston, MA, United States
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iPSC-Derived MSCs Are a Distinct Entity of MSCs with Higher Therapeutic Potential than Their Donor-Matched Parental MSCs. Int J Mol Sci 2023; 24:ijms24010881. [PMID: 36614321 PMCID: PMC9821152 DOI: 10.3390/ijms24010881] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/23/2022] [Accepted: 12/28/2022] [Indexed: 01/05/2023] Open
Abstract
Mesenchymal stromal cells derived from induced pluripotent stem cells (iMSCs) have been proposed as alternative sources of primary MSCs with various advantages for cell therapeutic trials. However, precise evaluation of the differences between iMSCs and primary MSCs is lacking due to individual variations in the donor cells, which obscure direct comparisons between the two. In this study, we generated donor-matched iMSCs from individual bone marrow-derived MSCs and directly compared their cell-autonomous and paracrine therapeutic effects. We found that the transition from primary MSCs to iMSCs is accompanied by a functional shift towards higher proliferative activity, with variations in differentiation potential in a donor cell-dependent manner. The transition from MSCs to iMSCs was associated with common changes in transcriptomic and proteomic profiles beyond the variations of their individual donors, revealing expression patterns unique for the iMSCs. These iMSC-specific patterns were characterized by a shift in cell fate towards a pericyte-like state and enhanced secretion of paracrine cytokine/growth factors. Accordingly, iMSCs exhibited higher support for the self-renewing expansion of primitive hematopoietic progenitors and more potent immune suppression of allogenic immune responses than MSCs. Our study suggests that iMSCs represent a separate entity of MSCs with unique therapeutic potential distinct from their parental MSCs, but points to the need for iMSC characterization in the individual basis.
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Sánchez‐Lanzas R, Kalampalika F, Ganuza M. Diversity in the bone marrow niche: Classic and novel strategies to uncover niche composition. Br J Haematol 2022; 199:647-664. [PMID: 35837798 PMCID: PMC9796334 DOI: 10.1111/bjh.18355] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/20/2022] [Accepted: 06/30/2022] [Indexed: 01/01/2023]
Abstract
Our view on the role and composition of the bone marrow (BM) has dramatically changed over time from a simple nutrient for the bone to a highly complex multicellular tissue that sustains haematopoiesis. Among these cells, multipotent haematopoietic stem cells (HSCs), which are predominantly quiescent, possess unique self-renewal capacity and multilineage differentiation potential and replenish all blood lineages to maintain lifelong haematopoiesis. Adult HSCs reside in specialised BM niches, which support their functions. Much effort has been put into deciphering HSC niches due to their potential clinical relevance. Multiple cell types have been implicated as HSC-niche components including sinusoidal endothelium, perivascular stromal cells, macrophages, megakaryocytes, osteoblasts and sympathetic nerves. In this review we provide a historical perspective on how technical advances, from genetic mouse models to imaging and high-throughput sequencing techniques, are unveiling the plethora of molecular cues and cellular components that shape the niche and regulate HSC functions.
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Affiliation(s)
- Raúl Sánchez‐Lanzas
- Centre for Haemato‐Oncology, Barts Cancer InstituteQueen Mary University of LondonLondonUK
| | - Foteini Kalampalika
- Centre for Haemato‐Oncology, Barts Cancer InstituteQueen Mary University of LondonLondonUK
| | - Miguel Ganuza
- Centre for Haemato‐Oncology, Barts Cancer InstituteQueen Mary University of LondonLondonUK
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Hua Y, Huo Y, Bai B, Hao J, Hu G, Ci Z, Wu X, Yu M, Wang X, Chen H, Ren W, Zhang Y, Wang X, Zhou G. Fabrication of biphasic cartilage-bone integrated scaffolds based on tissue-specific photo-crosslinkable acellular matrix hydrogels. Mater Today Bio 2022; 17:100489. [PMID: 36388453 PMCID: PMC9663535 DOI: 10.1016/j.mtbio.2022.100489] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/04/2022] [Accepted: 11/05/2022] [Indexed: 11/11/2022]
Abstract
The fabrication of biphasic cartilage-bone integrated scaffolds is an attractive alternative for osteochondral repair but has proven to be extremely challenging. Existing three-dimensional (3D) scaffolds are insufficient to accurately biomimic the biphasic cartilage-bone integrated microenvironment. Currently, photo-crosslinkable hydrogels based on tissue-specific decellularized extracellular matrix (dECM) have been considered as an important technique to fabricate biomimetic scaffolds, but so far there has been no breakthrough in the photo-crosslinkable hydrogel scaffolds with biphasic cartilage-bone biomimetic microenvironment. Here, we report a novel strategy for the preparation of biomimetic cartilage-bone integrated scaffolds based on photo-crosslinkable cartilage/bone-derived dECM hydrogels, which are able to reconstruct biphasic cartilage-bone biomimetic microenvironment. The biphasic cartilage-bone integrated scaffolds provided a 3D microenvironment for osteochondral regeneration. The cartilage biomimetic scaffolds, consisting of cartilage-derived dECM hydrogels, efficiently regulated chondrogenesis of bone marrow mesenchymal stem cells (BMSCs). The bone biomimetic scaffolds, composed of cartilage/bone-derived dECM hydrogels, first regulated chondrogenesis of BMSCs, followed by endochondral ossification over time. Taken together, the biphasic cartilage-bone integrated tissue could be successfully reconstructed by subcutaneous culture based on cartilage-bone bilayered structural design. Furthermore, the biphasic cartilage-bone biomimetic scaffolds (cell-free) achieved satisfactory cartilage-bone integrated regeneration in the osteochondral defects of rabbits’ knee joints.
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Affiliation(s)
- Yujie Hua
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, PR China
- National Tissue Engineering Center of China, Shanghai, PR China
- Institute of Regenerative Medicine and Orthopedics, Institutes of Health Central Plain, Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Yingying Huo
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, PR China
- National Tissue Engineering Center of China, Shanghai, PR China
| | - Baoshuai Bai
- Department of Orthopaedics, Qilu Hospital of Shangdong University Centre for Orthopaedics, Advanced Medical Research Institute, Shangdong University, Shangdong, PR China
| | - Junxiang Hao
- Research Institute of Plastic Surgery, Weifang Medical University, Weifang, Shandong, PR China
- National Tissue Engineering Center of China, Shanghai, PR China
| | - Guanhuai Hu
- Institute of Regenerative Medicine and Orthopedics, Institutes of Health Central Plain, Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Zheng Ci
- Research Institute of Plastic Surgery, Weifang Medical University, Weifang, Shandong, PR China
- National Tissue Engineering Center of China, Shanghai, PR China
| | - Xiaodi Wu
- Research Institute of Plastic Surgery, Weifang Medical University, Weifang, Shandong, PR China
- National Tissue Engineering Center of China, Shanghai, PR China
| | - Mengyuan Yu
- Institute of Regenerative Medicine and Orthopedics, Institutes of Health Central Plain, Xinxiang Medical University, Xinxiang, Henan, PR China
| | - Xin Wang
- Department of Hand Surgery, Ningbo Sixth Hospital, Zhejiang, PR China
| | - Hong Chen
- Department of Hand Surgery, Ningbo Sixth Hospital, Zhejiang, PR China
| | - Wenjie Ren
- Institute of Regenerative Medicine and Orthopedics, Institutes of Health Central Plain, Xinxiang Medical University, Xinxiang, Henan, PR China
- Corresponding author.
| | - Yixin Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, PR China
| | - Xiaoyun Wang
- Department of Plastic Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, PR China
- Corresponding author.
| | - Guangdong Zhou
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, PR China
- Research Institute of Plastic Surgery, Weifang Medical University, Weifang, Shandong, PR China
- National Tissue Engineering Center of China, Shanghai, PR China
- Institute of Regenerative Medicine and Orthopedics, Institutes of Health Central Plain, Xinxiang Medical University, Xinxiang, Henan, PR China
- Corresponding author. Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, PR China.
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Functional Heterogeneity of Bone Marrow Mesenchymal Stem Cell Subpopulations in Physiology and Pathology. Int J Mol Sci 2022; 23:ijms231911928. [PMID: 36233230 PMCID: PMC9570000 DOI: 10.3390/ijms231911928] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/26/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) are multi-potent cell populations and are capable of maintaining bone and body homeostasis. The stemness and potential therapeutic effect of BMSCs have been explored extensively in recent years. However, diverse cell surface antigens and complex gene expression of BMSCs have indicated that BMSCs represent heterogeneous populations, and the natural characteristics of BMSCs make it difficult to identify the specific subpopulations in pathological processes which are often obscured by bulk analysis of the total BMSCs. Meanwhile, the therapeutic effect of total BMSCs is often less effective partly due to their heterogeneity. Therefore, understanding the functional heterogeneity of the BMSC subpopulations under different physiological and pathological conditions could have major ramifications for global health. Here, we summarize the recent progress of functional heterogeneity of BMSC subpopulations in physiology and pathology. Targeting tissue-resident single BMSC subpopulation offers a potentially innovative therapeutic strategy and improves BMSC effectiveness in clinical application.
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Mastrolia I, Giorgini A, Murgia A, Loschi P, Petrachi T, Rasini V, Pinelli M, Pinto V, Lolli F, Chiavelli C, Grisendi G, Baschieri MC, Santis GD, Catani F, Dominici M, Veronesi E. Autologous Marrow Mesenchymal Stem Cell Driving Bone Regeneration in a Rabbit Model of Femoral Head Osteonecrosis. Pharmaceutics 2022; 14:pharmaceutics14102127. [PMID: 36297562 PMCID: PMC9610232 DOI: 10.3390/pharmaceutics14102127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/21/2022] [Accepted: 10/03/2022] [Indexed: 11/07/2022] Open
Abstract
Osteonecrosis of the femoral head (ONFH) is a progressive degenerative disease that ultimately requires a total hip replacement. Mesenchymal stromal/stem cells (MSCs), particularly the ones isolated from bone marrow (BM), could be promising tools to restore bone tissue in ONFH. Here, we established a rabbit model to mimic the pathogenic features of human ONFH and to challenge an autologous MSC-based treatment. ON has been originally induced by the synergic combination of surgery and steroid administration. Autologous BM-MSCs were then implanted in the FH, aiming to restore the damaged tissue. Histological analyses confirmed bone formation in the BM-MSC treated rabbit femurs but not in the controls. In addition, the model also allowed investigations on BM-MSCs isolated before (ON-BM-MSCs) and after (ON+BM-MSCs) ON induction to dissect the impact of ON damage on MSC behavior in an affected microenvironment, accounting for those clinical approaches foreseeing MSCs generally isolated from affected patients. BM-MSCs, isolated before and after ON induction, revealed similar growth rates, immunophenotypic profiles, and differentiation abilities regardless of the ON. Our data support the use of ON+BM-MSCs as a promising autologous therapeutic tool to treat ON, paving the way for a more consolidated use into the clinical settings.
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Affiliation(s)
- Ilenia Mastrolia
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy
- Correspondence:
| | - Andrea Giorgini
- Division of Orthopedics, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Alba Murgia
- Technopole of Mirandola TPM, Mirandola, 41037 Modena, Italy
| | | | | | - Valeria Rasini
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Massimo Pinelli
- Division of Plastic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Valentina Pinto
- Division of Plastic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Francesca Lolli
- Division of Plastic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Chiara Chiavelli
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Giulia Grisendi
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Maria Cristina Baschieri
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Giorgio De Santis
- Division of Plastic Surgery, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Fabio Catani
- Division of Orthopedics, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41124 Modena, Italy
| | - Massimo Dominici
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy
- Technopole of Mirandola TPM, Mirandola, 41037 Modena, Italy
| | - Elena Veronesi
- Laboratory of Cellular Therapy, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, 41124 Modena, Italy
- Technopole of Mirandola TPM, Mirandola, 41037 Modena, Italy
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Kim MJ, Valderrábano RJ, Wu JY. Osteoblast Lineage Support of Hematopoiesis in Health and Disease. J Bone Miner Res 2022; 37:1823-1842. [PMID: 35983701 PMCID: PMC11346465 DOI: 10.1002/jbmr.4678] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/21/2022] [Accepted: 08/13/2022] [Indexed: 11/06/2022]
Abstract
In mammals, hematopoiesis migrates to the bone marrow during embryogenesis coincident with the appearance of mineralized bone, where hematopoietic stem cells (HSCs) and their progeny are maintained by the surrounding microenvironment or niche, and sustain the entirety of the hematopoietic system. Genetic manipulation of niche factors and advances in cell lineage tracing techniques have implicated cells of both hematopoietic and nonhematopoietic origin as important regulators of hematopoiesis in health and disease. Among them, cells of the osteoblast lineage, from stromal skeletal stem cells to matrix-embedded osteocytes, are vital niche residents with varying capacities for hematopoietic support depending on stage of differentiation. Here, we review populations of osteoblasts at differing stages of differentiation and summarize the current understanding of the role of the osteoblast lineage in supporting hematopoiesis. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Matthew J Kim
- Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Rodrigo J Valderrábano
- Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Joy Y Wu
- Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Abstract
Lifestyle factors are modifiable behavioral factors that have a significant impact on health and longevity. Diet-induced obesity and physical activity/exercise are two prevalent lifestyle factors that have strong relationships to overall health. The mechanisms linking obesity to negative health outcomes and the mechanisms linking increased participation in physical activity/exercise to positive health outcomes are beginning to be elucidated. Chronic inflammation, due in part to overproduction of myeloid cells from hematopoietic stem cells (HSCs) in the bone marrow, is an established mechanism responsible for the negative health effects of obesity. Recent work has shown that exercise training can reverse the aberrant myelopoiesis present in obesity in part by restoring the bone marrow microenvironment. Specifically, exercise training reduces marrow adipose tissue, increases HSC retention factor expression, and reduces pro-inflammatory cytokine levels in the bone marrow. Other, novel mechanistic factors responsible for these exercise-induced effects, including intercellular communication using extracellular vesicles (EVs), is beginning to be explored. This review will summarize the recent literature describing the effects of exercise on hematopoiesis in individuals with obesity and introduce the potential contribution of EVs to this process.
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38
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Li L, Yang L, Chen X, Chen X, Diao L, Zeng Y, Xu J. TNFAIP6 defines the MSC subpopulation with enhanced immune suppression activities. STEM CELL RESEARCH & THERAPY 2022; 13:479. [PMID: 36153571 PMCID: PMC9509641 DOI: 10.1186/s13287-022-03176-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 09/11/2022] [Indexed: 11/30/2022]
Abstract
Background Mesenchymal stromal/stem cells (MSCs) have been intensively investigated in both pre-clinical and clinical studies. However, the therapeutic efficacy varies resulting from the heterogenicity of MSCs. Therefore, purifying the specific MSC subpopulation with specialized function is necessary for their therapeutic applications. Methods The large-scale RNA sequencing analysis was performed to identify potential cell markers for the mouse MSCs. Then, the immune suppression activities of the purified MSC subpopulation were assessed in vitro and in vivo.
Results The TNFAIP6 (tumor necrosis factor alpha-induced protein 6) has been identified as a potential cell marker for mouse MSCs, irrespective of tissue origin and laboratory origin. The TNFAIP6+ mouse MSCs showed enhanced immune suppression activities and improved therapeutic effects on the mouse model of acute inflammation, resulting from faster response to immune stimulation. Conclusions Therefore, we have demonstrated that the TNFAIP6+ MSC subpopulation has enhanced immune suppression capabilities. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03176-5.
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Karpenko D, Kapranov N, Bigildeev A. Nestin-GFP transgene labels immunoprivileged bone marrow mesenchymal stem cells in the model of ectopic foci formation. Front Cell Dev Biol 2022; 10:993056. [PMID: 36133916 PMCID: PMC9483855 DOI: 10.3389/fcell.2022.993056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Accepted: 08/09/2022] [Indexed: 11/13/2022] Open
Abstract
Immune privileges are demonstrated for different types of quiescent stem cells of adult mammalian organisms. Mesenchymal stem cells (MSCs) are believed to have immune privileges; however, an accurate experimental confirmation hasn’t been presented. Here, we provide direct experimental evidence that MSCs of C57Black/6J murine bone marrow (BM) are immune privileged in vivo and retain their functionality after prolonged exposure to the uncompromised immune system. The BM of Nes-Gfp transgenic mice was implanted as a tissue fragment under the kidney capsule in isogenic C57Black/6J immunocompetent recipients. Nestin-Gfp strain provides a fluorescent immunogenic marker for a small fraction of BM cells, including GFP+CD45– MSCs. Despite the exposure of xenogenically marked MSCs to the fully-functional immune system, primary ectopic foci of hematopoiesis formed. Six weeks after implantation, multicolor fluorescence cytometry revealed both GFP+CD45– and GFP+CD45+ cells within the foci. GFP+CD45– cells proportion was 2.0 × 10–5 ×÷9 and it didn’t differ significantly from syngenic Nes-GFP transplantation control. According to current knowledge, the immune system of the recipients should eliminate GFP+ cells, including GFP+ MSCs. These results show that MSCs evade immunity. Primary foci were retransplanted into secondary Nes-GFP recipients. The secondary foci formed, in which CD45–GFP+ cells proportion was 6.7 × 10–5 ×÷2.2, and it didn’t differ from intact Nes-GFP BM. The results demonstrate that MSCs preserve self-renewal and retain their functionality after prolonged immune exposure. The success of this study relied on the implantation of BM fragments without prior dissociation of cells and the fact that the vast majority of implanted cells were immunologically equivalent to the recipients.
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Affiliation(s)
- Dmitriy Karpenko
- Laboratory of Physiology of Hematopoiesis, National Medical Research Center for Hematology, Moscow, Russia
- *Correspondence: Aleksei Bigildeev, ; Karpenko Dmitriy,
| | - Nikolay Kapranov
- Immunophenotyping Department, National Medical Research Center for Hematology, Moscow, Russia
| | - Aleksei Bigildeev
- Laboratory of Physiology of Hematopoiesis, National Medical Research Center for Hematology, Moscow, Russia
- *Correspondence: Aleksei Bigildeev, ; Karpenko Dmitriy,
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Goodnough LH, Ambrosi TH, Steininger HM, Butler MGK, Hoover MY, Choo H, Van Rysselberghe NL, Bellino MJ, Bishop JA, Gardner MJ, Chan CKF. Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs. Front Endocrinol (Lausanne) 2022; 13:924927. [PMID: 36093067 PMCID: PMC9454294 DOI: 10.3389/fendo.2022.924927] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory. In this study, we prospectively isolated mouse and human skeletal stem cells (SSCs) from fractures and compared the effect of various NSAIDs on their function. We found that osteochondrogenic differentiation of COX2-expressing mouse SSCs was impaired by NSAID treatment. In contrast, human SSCs (hSSC) downregulated COX2 expression during differentiation and showed impaired osteogenic capacity if COX2 was lentivirally overexpressed. Accordingly, short- and long-term treatment of hSSCs with non-selective and selective COX2 inhibitors did not affect colony forming ability, chondrogenic, and osteogenic differentiation potential in vitro. When hSSCs were transplanted ectopically into NSG mice treated with Indomethacin, graft mineralization was unaltered compared to vehicle injected mice. Thus, our results might contribute to understanding species-specific differences in NSAID sensitivity during fracture healing and support emerging clinical data which conflicts with other earlier observations that NSAID administration for post-operative analgesia for treatment of bone fractures are unsafe for patients.
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Affiliation(s)
- L. Henry Goodnough
- Department of Orthopaedic Surgery, Stanford Hospitals and Clinics, Stanford, CA, United States
| | - Thomas H. Ambrosi
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States
| | - Holly M. Steininger
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - M. Gohazrua K. Butler
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Malachia Y. Hoover
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - HyeRan Choo
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States
| | | | - Michael J. Bellino
- Department of Orthopaedic Surgery, Stanford Hospitals and Clinics, Stanford, CA, United States
| | - Julius A. Bishop
- Department of Orthopaedic Surgery, Stanford Hospitals and Clinics, Stanford, CA, United States
| | - Michael J. Gardner
- Department of Orthopaedic Surgery, Stanford Hospitals and Clinics, Stanford, CA, United States
| | - Charles K. F. Chan
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States
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41
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Takihara Y, Higaki T, Yokomizo T, Umemoto T, Ariyoshi K, Hashimoto M, Sezaki M, Takizawa H, Inoue T, Suda T, Mizuno H. Bone marrow imaging reveals the migration dynamics of neonatal hematopoietic stem cells. Commun Biol 2022; 5:776. [PMID: 35918480 PMCID: PMC9346000 DOI: 10.1038/s42003-022-03733-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 07/15/2022] [Indexed: 12/03/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are produced from the blood vessel walls and circulate in the blood during the perinatal period. However, the migration dynamics of how HSCs enter the bone marrow remain elusive. To observe the dynamics of HSCs over time, the present study develops an intravital imaging method to visualize bone marrow in neonatal long bones formed by endochondral ossification which is essential for HSC niche formation. Endogenous HSCs are labeled with tdTomato under the control of an HSC marker gene Hlf, and a customized imaging system with a bone penetrating laser is developed for intravital imaging of tdTomato-labeled neonatal HSCs in undrilled tibia, which is essential to avoid bleeding from fragile neonatal tibia by bone drilling. The migration speed of neonatal HSCs is higher than that of adult HSCs. Neonatal HSCs migrate from outside to inside the tibia via the blood vessels that penetrate the bone, which is a transient structure during the neonatal period, and settle on the blood vessel wall in the bone marrow. The results obtained from direct observations in vivo reveal the motile dynamics and colonization process of neonatal HSCs during bone marrow formation. An intravital imaging method reveals the in vivo motile dynamics and colonization process of neonatal hematopoietic stem cells during bone marrow formation.
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Affiliation(s)
- Yuji Takihara
- Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan.,Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, 117599, Singapore, Singapore
| | - Takumi Higaki
- Graduate School of Science and Technology, Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto, Japan.,International Research Organization for Advanced Science and Technology (IROAST), Kumamoto University, 2-39-1 Kurokami, Chuo-ku, Kumamoto, Japan
| | - Tomomasa Yokomizo
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, Japan
| | - Terumasa Umemoto
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, Japan
| | - Kazunori Ariyoshi
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, Japan
| | - Michihiro Hashimoto
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, Japan
| | - Maiko Sezaki
- International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, Japan
| | - Hitoshi Takizawa
- Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan.,International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, Japan
| | - Toshihiro Inoue
- Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan
| | - Toshio Suda
- Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, 117599, Singapore, Singapore. .,International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, Japan.
| | - Hidenobu Mizuno
- Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, Japan. .,International Research Center for Medical Sciences (IRCMS), Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, Japan.
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42
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Zou N, Liu R, Li C. Cathepsin K+ Non-Osteoclast Cells in the Skeletal System: Function, Models, Identity, and Therapeutic Implications. Front Cell Dev Biol 2022; 10:818462. [PMID: 35912093 PMCID: PMC9326176 DOI: 10.3389/fcell.2022.818462] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
Cathepsin K (Ctsk) is a cysteine protease of the papain superfamily initially identified in differentiated osteoclasts; it plays a critical role in degrading the bone matrix. However, subsequent in vivo and in vitro studies based on animal models elucidate novel subpopulations of Ctsk-expressing cells, which display markers and properties of mesenchymal stem/progenitor cells. This review introduces the function, identity, and role of Ctsk+ cells and their therapeutic implications in related preclinical osseous disorder models. It also summarizes the available in vivo models for studying Ctsk+ cells and their progeny. Further investigations of detailed properties and mechanisms of Ctsk+ cells in transgenic models are required to guide potential therapeutic targets in multiple diseases in the future.
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Affiliation(s)
- Nanyu Zou
- Department of Endocrinology, Endocrinology Research Center, The Xiangya Hospital of Central South University, Changsha, China
| | - Ran Liu
- Department of Endocrinology, Endocrinology Research Center, The Xiangya Hospital of Central South University, Changsha, China
| | - Changjun Li
- Department of Endocrinology, Endocrinology Research Center, The Xiangya Hospital of Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders (Xiangya Hospital), Changsha, China
- Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, China
- *Correspondence: Changjun Li,
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43
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Liu Y, Lin D, Li B, Hong H, Jiang C, Yuan Y, Wang J, Hu R, Li B, Liu C. BMP-2/CPC scaffold with dexamethasone-loaded blood clot embedment accelerates clinical bone regeneration. Am J Transl Res 2022; 14:2874-2893. [PMID: 35702132 PMCID: PMC9185047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/31/2022] [Indexed: 06/15/2023]
Abstract
Delayed repair caused by prolonged inflammatory response might lead to clinical nonunion and failed bone regeneration. The design of desirable biomaterials requires precise regulation of the initial osteoimmune responses and efficient osteoinductive capacity to facilitate later bone regeneration. Herein, a Dex-loaded blood clot-embedded BMP-2/CPC scaffold (Dex/blood/BMP-2/CPC) was fabricated for clinical bone regeneration with the sequential release of dexamethasone (Dex), a clinical immunosuppression drug, and BMP-2, a potent osteogenic growth factor. The introduction of Dex at a BMP-2/Dex ratio of 1/6 effectively facilitated M2 polarization of macrophages and exerted a synergetic effect on BMP-2-mediated osteogenic differentiation. The highest in vivo bone regenerative efficacy was achieved by Dex/blood/BMP-2/CPC scaffold with a 1/6 BMP-2/Dex dose, exhibiting significantly enhanced endochondral ossification and attenuated bone resorption in an ectopic model, as well as reduced fibrosis at the orthotopic defect site. Blood clot embedment further provides nutrition and cytokines for the endochondral ossification process. On these bases, a pilot clinical trial was carried out and the Dex/blood/BMP-2/CPC scaffold was demonstrated to accelerate fracture healing, improve therapeutic quality, and eliminate local inflammation compared to current bone regenerative treatment. Taken together, this work designed an immunoregulatory and osteoinductive Dex/blood/BMP-2/CPC scaffold, which might provide new insights for future biomaterial development (Trial registration: ChiCTR2100047693).
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Affiliation(s)
- Yutong Liu
- Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and TechnologyShanghai, China
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and TechnologyShanghai, China
| | - Dan Lin
- Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and TechnologyShanghai, China
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and TechnologyShanghai, China
| | - Bo Li
- Department of Orthopaedics, Guizhou Provincial People’s HospitalGuiyang 550002, China
| | - Hua Hong
- Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and TechnologyShanghai, China
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and TechnologyShanghai, China
| | - Chuan Jiang
- Department of Orthopaedic Surgery, Ninth People’s Hospital of Shanghai Jiao Tong UniversityShanghai 200011, China
| | - Yuan Yuan
- Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and TechnologyShanghai, China
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and TechnologyShanghai, China
| | - Jinwu Wang
- Department of Orthopaedic Surgery, Ninth People’s Hospital of Shanghai Jiao Tong UniversityShanghai 200011, China
| | - Ruyin Hu
- Department of Orthopaedics, Guizhou Provincial People’s HospitalGuiyang 550002, China
| | - Bo Li
- Department of Orthopaedics, Guizhou Provincial People’s HospitalGuiyang 550002, China
| | - Changsheng Liu
- Engineering Research Center for Biomaterials of Ministry of Education, East China University of Science and TechnologyShanghai, China
- Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and TechnologyShanghai, China
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44
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Hughes AM, Kuek V, Kotecha RS, Cheung LC. The Bone Marrow Microenvironment in B-Cell Development and Malignancy. Cancers (Basel) 2022; 14:2089. [PMID: 35565219 PMCID: PMC9102980 DOI: 10.3390/cancers14092089] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/11/2022] [Accepted: 04/20/2022] [Indexed: 11/16/2022] Open
Abstract
B lymphopoiesis is characterized by progressive loss of multipotent potential in hematopoietic stem cells, followed by commitment to differentiate into B cells, which mediate the humoral response of the adaptive immune system. This process is tightly regulated by spatially distinct bone marrow niches where cells, including mesenchymal stem and progenitor cells, endothelial cells, osteoblasts, osteoclasts, and adipocytes, interact with B-cell progenitors to direct their proliferation and differentiation. Recently, the B-cell niche has been implicated in initiating and facilitating B-cell precursor acute lymphoblastic leukemia. Leukemic cells are also capable of remodeling the B-cell niche to promote their growth and survival and evade treatment. Here, we discuss the major cellular components of bone marrow niches for B lymphopoiesis and the role of the malignant B-cell niche in disease development, treatment resistance and relapse. Further understanding of the crosstalk between leukemic cells and bone marrow niche cells will enable development of additional therapeutic strategies that target the niches in order to hinder leukemia progression.
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Affiliation(s)
- Anastasia M. Hughes
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
| | - Vincent Kuek
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- School of Biomedical Sciences, University of Western Australia, Perth, WA 6009, Australia
| | - Rishi S. Kotecha
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- School of Medicine, University of Western Australia, Perth, WA 6009, Australia
- Department of Clinical Haematology, Oncology, Blood and Marrow Transplantation, Perth Children’s Hospital, Perth, WA 6009, Australia
| | - Laurence C. Cheung
- Leukaemia Translational Research Laboratory, Telethon Kids Cancer Centre, Telethon Kids Institute, Perth, WA 6009, Australia; (A.M.H.); (V.K.); (R.S.K.)
- Curtin Medical School, Curtin University, Perth, WA 6102, Australia
- Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia
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45
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Kandarakov O, Belyavsky A, Semenova E. Bone Marrow Niches of Hematopoietic Stem and Progenitor Cells. Int J Mol Sci 2022; 23:ijms23084462. [PMID: 35457280 PMCID: PMC9032554 DOI: 10.3390/ijms23084462] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 12/15/2022] Open
Abstract
The mammalian hematopoietic system is remarkably efficient in meeting an organism’s vital needs, yet is highly sensitive and exquisitely regulated. Much of the organismal control over hematopoiesis comes from the regulation of hematopoietic stem cells (HSCs) by specific microenvironments called niches in bone marrow (BM), where HSCs reside. The experimental studies of the last two decades using the most sophisticated and advanced techniques have provided important data on the identity of the niche cells controlling HSCs functions and some mechanisms underlying niche-HSC interactions. In this review we discuss various aspects of organization and functioning of the HSC cell niche in bone marrow. In particular, we review the anatomy of BM niches, various cell types composing the niche, niches for more differentiated cells, metabolism of HSCs in relation to the niche, niche aging, leukemic transformation of the niche, and the current state of HSC niche modeling in vitro.
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46
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Little-Letsinger SE, Rubin J, Diekman B, Rubin CT, McGrath C, Pagnotti GM, Klett EL, Styner M. Exercise to Mend Aged-tissue Crosstalk in Bone Targeting Osteoporosis & Osteoarthritis. Semin Cell Dev Biol 2022; 123:22-35. [PMID: 34489173 PMCID: PMC8840966 DOI: 10.1016/j.semcdb.2021.08.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 08/16/2021] [Accepted: 08/19/2021] [Indexed: 12/16/2022]
Abstract
Aging induces alterations in bone structure and strength through a multitude of processes, exacerbating common aging- related diseases like osteoporosis and osteoarthritis. Cellular hallmarks of aging are examined, as related to bone and the marrow microenvironment, and ways in which these might contribute to a variety of age-related perturbations in osteoblasts, osteocytes, marrow adipocytes, chondrocytes, osteoclasts, and their respective progenitors. Cellular senescence, stem cell exhaustion, mitochondrial dysfunction, epigenetic and intracellular communication changes are central pathways and recognized as associated and potentially causal in aging. We focus on these in musculoskeletal system and highlight knowledge gaps in the literature regarding cellular and tissue crosstalk in bone, cartilage, and the bone marrow niche. While senolytics have been utilized to target aging pathways, here we propose non-pharmacologic, exercise-based interventions as prospective "senolytics" against aging effects on the skeleton. Increased bone mass and delayed onset or progression of osteoporosis and osteoarthritis are some of the recognized benefits of regular exercise across the lifespan. Further investigation is needed to delineate how cellular indicators of aging manifest in bone and the marrow niche and how altered cellular and tissue crosstalk impact disease progression, as well as consideration of exercise as a therapeutic modality, as a means to enhance discovery of bone-targeted therapies.
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Affiliation(s)
- SE Little-Letsinger
- Department of Medicine, Division of Endocrinology & Metabolism, University of North Carolina at Chapel Hill
| | - J Rubin
- Department of Medicine, Division of Endocrinology & Metabolism, University of North Carolina at Chapel Hill,North Carolina Diabetes Research Center (NCDRC), University of North Carolina at Chapel Hill,Department of Medicine, Thurston Arthritis Research Center (TARC), University of North Carolina at Chapel Hill
| | - B Diekman
- Department of Medicine, Thurston Arthritis Research Center (TARC), University of North Carolina at Chapel Hill,Joint Departments of Biomedical Engineering NC State & University of North Carolina at Chapel Hill
| | - CT Rubin
- Department of Biomedical Engineering, State University of New York at Stony Brook
| | - C McGrath
- Department of Medicine, Division of Endocrinology & Metabolism, University of North Carolina at Chapel Hill
| | - GM Pagnotti
- Dept of Endocrine, Neoplasia, and Hormonal Disorders, University Texas MD Anderson Cancer Center, Houston
| | - EL Klett
- Department of Medicine, Division of Endocrinology & Metabolism, University of North Carolina at Chapel Hill,Department of Nutrition, School of Public Health, University of North Carolina at Chapel Hill
| | - M Styner
- Department of Medicine, Division of Endocrinology & Metabolism, University of North Carolina at Chapel Hill,North Carolina Diabetes Research Center (NCDRC), University of North Carolina at Chapel Hill,Department of Medicine, Thurston Arthritis Research Center (TARC), University of North Carolina at Chapel Hill
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47
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Mo C, Guo J, Qin J, Zhang X, Sun Y, Wei H, Cao D, Zhang Y, Zhao C, Xiong Y, Zhang Y, Sun Y, Shen L, Yue R. Single-cell transcriptomics of LepR-positive skeletal cells reveals heterogeneous stress-dependent stem and progenitor pools. EMBO J 2022; 41:e108415. [PMID: 34957577 PMCID: PMC8844986 DOI: 10.15252/embj.2021108415] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 12/31/2022] Open
Abstract
Leptin receptor (LepR)-positive cells are key components of the bone marrow hematopoietic microenvironment, and highly enrich skeletal stem and progenitor cells that maintain homeostasis of the adult skeleton. However, the heterogeneity and lineage hierarchy within this population has been elusive. Using genetic lineage tracing and single-cell RNA sequencing, we found that Lepr-Cre labels most bone marrow stromal cells and osteogenic lineage cells in adult long bones. Integrated analysis of Lepr-Cre-traced cells under homeostatic and stress conditions revealed dynamic changes of the adipogenic, osteogenic, and periosteal lineages. Importantly, we discovered a Notch3+ bone marrow sub-population that is slow-cycling and closely associated with the vasculatures, as well as key transcriptional networks promoting osteo-chondrogenic differentiation. We also identified a Sca-1+ periosteal sub-population with high clonogenic activity but limited osteo-chondrogenic potential. Together, we mapped the transcriptomic landscape of adult LepR+ stem and progenitor cells and uncovered cellular and molecular mechanisms underlying their maintenance and lineage specification.
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Affiliation(s)
- Chunyang Mo
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Jingxin Guo
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences InstituteZhejiang UniversityHangzhouChina
- Department of Orthopedics Surgery2nd Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
| | - Jiachen Qin
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Xiaoying Zhang
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Yuxi Sun
- Department of CardiologyShanghai Tenth People's HospitalTongji University School of MedicineShanghaiChina
| | - Hanjing Wei
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Dandan Cao
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Yiying Zhang
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Chengchen Zhao
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Yanhong Xiong
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Yong Zhang
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
| | - Yao Sun
- Department of ImplantologySchool & Hospital of StomatologyShanghai Engineering Research Center of Tooth Restoration and RegenerationTongji UniversityShanghaiChina
| | - Li Shen
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences InstituteZhejiang UniversityHangzhouChina
- Department of Orthopedics Surgery2nd Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouChina
- Hangzhou Innovation CenterZhejiang UniversityHangzhouChina
| | - Rui Yue
- Institute for Regenerative MedicineShanghai East HospitalFrontier Science Center for Stem Cell ResearchShanghai Key Laboratory of Signaling and Disease ResearchSchool of Life Sciences and TechnologyTongji UniversityShanghaiChina
- Shanghai Institute of Stem Cell Research and Clinical TranslationShanghaiChina
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48
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Dai K, Deng S, Yu Y, Zhu F, Wang J, Liu C. Construction of developmentally inspired periosteum-like tissue for bone regeneration. Bone Res 2022; 10:1. [PMID: 34975148 PMCID: PMC8720863 DOI: 10.1038/s41413-021-00166-w] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 05/19/2021] [Accepted: 06/08/2021] [Indexed: 12/15/2022] Open
Abstract
The periosteum, a highly vascularized thin tissue, has excellent osteogenic and bone regenerative abilities. The generation of periosteum-mimicking tissue has become a novel strategy for bone defect repair and regeneration, especially in critical-sized bone defects caused by trauma and bone tumor resection. Here, we utilized a bone morphogenetic protein-2 (BMP-2)-loaded scaffold to create periosteum-like tissue (PT) in vivo, mimicking the mesenchymal condensation during native long bone development. We found that BMP-2-induced endochondral ossification plays an indispensable role in the construction of PTs. Moreover, we confirmed that BMP-2-induced PTs exhibit a similar architecture to the periosteum and harbor abundant functional periosteum-like tissue-derived cells (PTDCs), blood vessels, and osteochondral progenitor cells. Interestingly, we found that the addition of chondroitin sulfate (CS), an essential component of the extracellular matrix (ECM), could further increase the abundance and enhance the function of recruited PTDCs from the PTs and finally increase the regenerative capacity of the PTs in autologous transplantation assays, even in old mice. This novel biomimetic strategy for generating PT through in vivo endochondral ossification deserves further clinical translation.
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Affiliation(s)
- Kai Dai
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, P. R. China.,Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China
| | - Shunshu Deng
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, P. R. China.,Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China
| | - Yuanman Yu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, P. R. China.,Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China
| | - Fuwei Zhu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, P. R. China.,Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China
| | - Jing Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, P. R. China. .,Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China.
| | - Changsheng Liu
- Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China. .,Key Laboratory for Ultrafine Materials of Ministry of Education, East China University of Science and Technology, Shanghai, P. R. China. .,Frontiers Science Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, Shanghai, P. R. China.
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49
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Chen Y, Miao Y, Liu K, Xue F, Zhu B, Zhang C, Li G. Evolutionary course of the femoral head osteonecrosis: Histopathological - radiologic characteristics and clinical staging systems. J Orthop Translat 2022; 32:28-40. [PMID: 35591937 PMCID: PMC9072800 DOI: 10.1016/j.jot.2021.07.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/26/2021] [Accepted: 07/26/2021] [Indexed: 02/07/2023] Open
Abstract
Osteonecrosis of the femoral head (ONFH) is a recalcitrant ischemic disorder, which could be classified into two major categories: traumatic and nontraumatic. Regardless of different risk factors, it has been testified that ONFH results from primitive vascular problems, leading to temporary or permanent loss of blood supply to bone tissue. Histopathological and microarchitectural alterations ensues, which is a gradual evolutionary process involving bone marrow and osteocyte necrosis, progressive destruction of subchondral bone, unsuccessful reparative process, and eventual articular collapse and degenerative arthritis. Based on the imaging features of ONFH, different classification systems have been developed to evaluate the severity and prognosis of the disease, which is pivotal for implementation of treatment strategy, especially the joint-preserving surgery. However, patients classified with the same severity stage, especially in the peri-collapse stage, sometimes responded differently after similar joint-preserving surgery. The unusual phenomenon may be attributed to the limitation of the current imaging classification systems, which might underestimate the disease severity, especially when referring to the early stages. In this review, we briefly summarize the etiology and pathogenesis of ONFH. The imaging features and staging classification systems of ONFH are also described. More importantly, we focus on histopathological and microstructural alterations of the femoral head, and provide an overview of their essential contribution to ONFH progression. Given the observation of discordance between imaging characteristics and histopathological alterations, a substantial amount of research on the relationship between imaging and histopathological features is required to further modify and revise the current wide-accepted classification systems.
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Cossarizza A, Chang HD, Radbruch A, Abrignani S, Addo R, Akdis M, Andrä I, Andreata F, Annunziato F, Arranz E, Bacher P, Bari S, Barnaba V, Barros-Martins J, Baumjohann D, Beccaria CG, Bernardo D, Boardman DA, Borger J, Böttcher C, Brockmann L, Burns M, Busch DH, Cameron G, Cammarata I, Cassotta A, Chang Y, Chirdo FG, Christakou E, Čičin-Šain L, Cook L, Corbett AJ, Cornelis R, Cosmi L, Davey MS, De Biasi S, De Simone G, del Zotto G, Delacher M, Di Rosa F, Di Santo J, Diefenbach A, Dong J, Dörner T, Dress RJ, Dutertre CA, Eckle SBG, Eede P, Evrard M, Falk CS, Feuerer M, Fillatreau S, Fiz-Lopez A, Follo M, Foulds GA, Fröbel J, Gagliani N, Galletti G, Gangaev A, Garbi N, Garrote JA, Geginat J, Gherardin NA, Gibellini L, Ginhoux F, Godfrey DI, Gruarin P, Haftmann C, Hansmann L, Harpur CM, Hayday AC, Heine G, Hernández DC, Herrmann M, Hoelsken O, Huang Q, Huber S, Huber JE, Huehn J, Hundemer M, Hwang WYK, Iannacone M, Ivison SM, Jäck HM, Jani PK, Keller B, Kessler N, Ketelaars S, Knop L, Knopf J, Koay HF, Kobow K, Kriegsmann K, Kristyanto H, Krueger A, Kuehne JF, Kunze-Schumacher H, Kvistborg P, Kwok I, Latorre D, et alCossarizza A, Chang HD, Radbruch A, Abrignani S, Addo R, Akdis M, Andrä I, Andreata F, Annunziato F, Arranz E, Bacher P, Bari S, Barnaba V, Barros-Martins J, Baumjohann D, Beccaria CG, Bernardo D, Boardman DA, Borger J, Böttcher C, Brockmann L, Burns M, Busch DH, Cameron G, Cammarata I, Cassotta A, Chang Y, Chirdo FG, Christakou E, Čičin-Šain L, Cook L, Corbett AJ, Cornelis R, Cosmi L, Davey MS, De Biasi S, De Simone G, del Zotto G, Delacher M, Di Rosa F, Di Santo J, Diefenbach A, Dong J, Dörner T, Dress RJ, Dutertre CA, Eckle SBG, Eede P, Evrard M, Falk CS, Feuerer M, Fillatreau S, Fiz-Lopez A, Follo M, Foulds GA, Fröbel J, Gagliani N, Galletti G, Gangaev A, Garbi N, Garrote JA, Geginat J, Gherardin NA, Gibellini L, Ginhoux F, Godfrey DI, Gruarin P, Haftmann C, Hansmann L, Harpur CM, Hayday AC, Heine G, Hernández DC, Herrmann M, Hoelsken O, Huang Q, Huber S, Huber JE, Huehn J, Hundemer M, Hwang WYK, Iannacone M, Ivison SM, Jäck HM, Jani PK, Keller B, Kessler N, Ketelaars S, Knop L, Knopf J, Koay HF, Kobow K, Kriegsmann K, Kristyanto H, Krueger A, Kuehne JF, Kunze-Schumacher H, Kvistborg P, Kwok I, Latorre D, Lenz D, Levings MK, Lino AC, Liotta F, Long HM, Lugli E, MacDonald KN, Maggi L, Maini MK, Mair F, Manta C, Manz RA, Mashreghi MF, Mazzoni A, McCluskey J, Mei HE, Melchers F, Melzer S, Mielenz D, Monin L, Moretta L, Multhoff G, Muñoz LE, Muñoz-Ruiz M, Muscate F, Natalini A, Neumann K, Ng LG, Niedobitek A, Niemz J, Almeida LN, Notarbartolo S, Ostendorf L, Pallett LJ, Patel AA, Percin GI, Peruzzi G, Pinti M, Pockley AG, Pracht K, Prinz I, Pujol-Autonell I, Pulvirenti N, Quatrini L, Quinn KM, Radbruch H, Rhys H, Rodrigo MB, Romagnani C, Saggau C, Sakaguchi S, Sallusto F, Sanderink L, Sandrock I, Schauer C, Scheffold A, Scherer HU, Schiemann M, Schildberg FA, Schober K, Schoen J, Schuh W, Schüler T, Schulz AR, Schulz S, Schulze J, Simonetti S, Singh J, Sitnik KM, Stark R, Starossom S, Stehle C, Szelinski F, Tan L, Tarnok A, Tornack J, Tree TIM, van Beek JJP, van de Veen W, van Gisbergen K, Vasco C, Verheyden NA, von Borstel A, Ward-Hartstonge KA, Warnatz K, Waskow C, Wiedemann A, Wilharm A, Wing J, Wirz O, Wittner J, Yang JHM, Yang J. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition). Eur J Immunol 2021; 51:2708-3145. [PMID: 34910301 PMCID: PMC11115438 DOI: 10.1002/eji.202170126] [Show More Authors] [Citation(s) in RCA: 272] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.
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Affiliation(s)
- Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Hyun-Dong Chang
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Institute for Biotechnology, Technische Universität, Berlin, Germany
| | - Andreas Radbruch
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Sergio Abrignani
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Richard Addo
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | - Immanuel Andrä
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
| | - Francesco Andreata
- Division of Immunology, Transplantation and Infectious Diseases, IRCSS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Annunziato
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Eduardo Arranz
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
| | - Petra Bacher
- Institute of Immunology, Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
- Institute of Clinical Molecular Biology Christian-Albrechts Universität zu Kiel, Kiel, Germany
| | - Sudipto Bari
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore
- Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
| | - Vincenzo Barnaba
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
- Center for Life Nano & Neuro Science@Sapienza, Istituto Italiano di Tecnologia (IIT), Rome, Italy
- Istituto Pasteur - Fondazione Cenci Bolognetti, Rome, Italy
| | | | - Dirk Baumjohann
- Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Cristian G. Beccaria
- Division of Immunology, Transplantation and Infectious Diseases, IRCSS San Raffaele Scientific Institute, Milan, Italy
| | - David Bernardo
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
- Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Dominic A. Boardman
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Jessica Borger
- Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia
| | - Chotima Böttcher
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Leonie Brockmann
- Department of Microbiology & Immunology, Columbia University, New York City, USA
| | - Marie Burns
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Dirk H. Busch
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Garth Cameron
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Ilenia Cammarata
- Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy
| | - Antonino Cassotta
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
| | - Yinshui Chang
- Medical Clinic III for Oncology, Hematology, Immuno-Oncology and Rheumatology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Fernando Gabriel Chirdo
- Instituto de Estudios Inmunológicos y Fisiopatológicos - IIFP (UNLP-CONICET), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina
| | - Eleni Christakou
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
| | - Luka Čičin-Šain
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Laura Cook
- BC Children’s Hospital Research Institute, Vancouver, Canada
- Department of Medicine, The University of British Columbia, Vancouver, Canada
| | - Alexandra J. Corbett
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Rebecca Cornelis
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Lorenzo Cosmi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Martin S. Davey
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Sara De Biasi
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Gabriele De Simone
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | - Michael Delacher
- Institute for Immunology, University Medical Center Mainz, Mainz, Germany
- Research Centre for Immunotherapy, University Medical Center Mainz, Mainz, Germany
| | - Francesca Di Rosa
- Institute of Molecular Biology and Pathology, National Research Council of Italy (CNR), Rome, Italy
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - James Di Santo
- Innate Immunity Unit, Department of Immunology, Institut Pasteur, Paris, France
- Inserm U1223, Paris, France
| | - Andreas Diefenbach
- Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Mucosal and Developmental Immunology, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Jun Dong
- Cell Biology, German Rheumatism Research Center Berlin (DRFZ), An Institute of the Leibniz Association, Berlin, Germany
| | - Thomas Dörner
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Regine J. Dress
- Institute of Systems Immunology, Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Charles-Antoine Dutertre
- Institut National de la Sante Et de la Recherce Medicale (INSERM) U1015, Equipe Labellisee-Ligue Nationale contre le Cancer, Villejuif, France
| | - Sidonia B. G. Eckle
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Pascale Eede
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Maximilien Evrard
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
| | - Christine S. Falk
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Markus Feuerer
- Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
- Chair for Immunology, University Regensburg, Regensburg, Germany
| | - Simon Fillatreau
- Institut Necker Enfants Malades, INSERM U1151-CNRS, UMR8253, Paris, France
- Université de Paris, Paris Descartes, Faculté de Médecine, Paris, France
- AP-HP, Hôpital Necker Enfants Malades, Paris, France
| | - Aida Fiz-Lopez
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
| | - Marie Follo
- Department of Medicine I, Lighthouse Core Facility, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Gemma A. Foulds
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Julia Fröbel
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
| | - Nicola Gagliani
- Department of Medicine, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Germany
| | - Giovanni Galletti
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Anastasia Gangaev
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Natalio Garbi
- Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany
| | - José Antonio Garrote
- Mucosal Immunology Lab, Unidad de Excelencia Instituto de Biomedicina y Genética Molecular de Valladolid (IBGM, Universidad de Valladolid-CSIC), Valladolid, Spain
- Laboratory of Molecular Genetics, Servicio de Análisis Clínicos, Hospital Universitario Río Hortega, Gerencia Regional de Salud de Castilla y León (SACYL), Valladolid, Spain
| | - Jens Geginat
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy
| | - Nicholas A. Gherardin
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Lara Gibellini
- Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
| | - Dale I. Godfrey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Paola Gruarin
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Claudia Haftmann
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Leo Hansmann
- Department of Hematology, Oncology, and Tumor Immunology, Charité - Universitätsmedizin Berlin (CVK), Berlin, Germany
- Berlin Institute of Health (BIH), Berlin, Germany
- German Cancer Consortium (DKTK), partner site Berlin, Germany
| | - Christopher M. Harpur
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia
- Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia
| | - Adrian C. Hayday
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - Guido Heine
- Division of Allergy, Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Daniela Carolina Hernández
- Innate Immunity, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases, Rheumatology, Berlin, Germany
| | - Martin Herrmann
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Oliver Hoelsken
- Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Mucosal and Developmental Immunology, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Qing Huang
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Samuel Huber
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johanna E. Huber
- Institute for Immunology, Biomedical Center, Faculty of Medicine, LMU Munich, Planegg-Martinsried, Germany
| | - Jochen Huehn
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Michael Hundemer
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - William Y. K. Hwang
- Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore
- Department of Hematology, Singapore General Hospital, Singapore, Singapore
- Executive Offices, National Cancer Centre Singapore, Singapore
| | - Matteo Iannacone
- Division of Immunology, Transplantation and Infectious Diseases, IRCSS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Sabine M. Ivison
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Hans-Martin Jäck
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Peter K. Jani
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Baerbel Keller
- Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Nina Kessler
- Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany
| | - Steven Ketelaars
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Laura Knop
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany
| | - Jasmin Knopf
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Hui-Fern Koay
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
- Australian Research Council Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Victoria, Australia
| | - Katja Kobow
- Department of Neuropathology, Universitätsklinikum Erlangen, Germany
| | - Katharina Kriegsmann
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - H. Kristyanto
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Andreas Krueger
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Jenny F. Kuehne
- Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany
| | - Heike Kunze-Schumacher
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Pia Kvistborg
- Division of Molecular Oncology and Immunology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Immanuel Kwok
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
| | | | - Daniel Lenz
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Megan K. Levings
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
- School of Biomedical Engineering, The University of British Columbia, Vancouver, Canada
| | - Andreia C. Lino
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Francesco Liotta
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Heather M. Long
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Enrico Lugli
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Katherine N. MacDonald
- BC Children’s Hospital Research Institute, Vancouver, Canada
- School of Biomedical Engineering, The University of British Columbia, Vancouver, Canada
- Michael Smith Laboratories, The University of British Columbia, Vancouver, Canada
| | - Laura Maggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Mala K. Maini
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Florian Mair
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Calin Manta
- Department of Hematology, Oncology and Rheumatology, University Heidelberg, Heidelberg, Germany
| | - Rudolf Armin Manz
- Institute for Systemic Inflammation Research, University of Luebeck, Luebeck, Germany
| | | | - Alessio Mazzoni
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - James McCluskey
- Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia
| | - Henrik E. Mei
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Fritz Melchers
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Susanne Melzer
- Clinical Trial Center Leipzig, Leipzig University, Härtelstr.16, −18, Leipzig, 04107, Germany
| | - Dirk Mielenz
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Leticia Monin
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - Lorenzo Moretta
- Department of Immunology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Gabriele Multhoff
- Radiation Immuno-Oncology Group, Center for Translational Cancer Research (TranslaTUM), Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany
- Department of Radiation Oncology, Technical University of Munich (TUM), Klinikum rechts der Isar, Munich, Germany
| | - Luis Enrique Muñoz
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Miguel Muñoz-Ruiz
- Immunosurveillance Laboratory, The Francis Crick Institute, London, UK
| | - Franziska Muscate
- Department of Medicine, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ambra Natalini
- Institute of Molecular Biology and Pathology, National Research Council of Italy (CNR), Rome, Italy
| | - Katrin Neumann
- Institute of Experimental Immunology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Lai Guan Ng
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
- Department of Microbiology & Immunology, Immunology Programme, Life Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | | | - Jana Niemz
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | | | - Samuele Notarbartolo
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Lennard Ostendorf
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Laura J. Pallett
- Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK
| | - Amit A. Patel
- Institut National de la Sante Et de la Recherce Medicale (INSERM) U1015, Equipe Labellisee-Ligue Nationale contre le Cancer, Villejuif, France
| | - Gulce Itir Percin
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
| | - Giovanna Peruzzi
- Center for Life Nano & Neuro Science@Sapienza, Istituto Italiano di Tecnologia (IIT), Rome, Italy
| | - Marcello Pinti
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - A. Graham Pockley
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, UK
- Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, UK
| | - Katharina Pracht
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Immo Prinz
- Institute of Immunology, Hannover Medical School, Hannover, Germany
- Institute of Systems Immunology, Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Irma Pujol-Autonell
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
- Peter Gorer Department of Immunobiology, King’s College London, London, UK
| | - Nadia Pulvirenti
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Linda Quatrini
- Department of Immunology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Kylie M. Quinn
- School of Biomedical and Health Sciences, RMIT University, Bundorra, Victoria, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Helena Radbruch
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Hefin Rhys
- Flow Cytometry Science Technology Platform, The Francis Crick Institute, London, UK
| | - Maria B. Rodrigo
- Institute of Molecular Medicine and Experimental Immunology, Faculty of Medicine, University of Bonn, Germany
| | - Chiara Romagnani
- Innate Immunity, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases, Rheumatology, Berlin, Germany
| | - Carina Saggau
- Institute of Immunology, Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
| | | | - Federica Sallusto
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland
- Institute of Microbiology, ETH Zurich, Zurich, Switzerland
| | - Lieke Sanderink
- Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany
- Chair for Immunology, University Regensburg, Regensburg, Germany
| | - Inga Sandrock
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - Christine Schauer
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Alexander Scheffold
- Institute of Immunology, Christian-Albrechts Universität zu Kiel & Universitätsklinik Schleswig-Holstein, Kiel, Germany
| | - Hans U. Scherer
- Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
| | - Matthias Schiemann
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
| | - Frank A. Schildberg
- Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
| | - Kilian Schober
- Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, Munich, Germany
- Mikrobiologisches Institut – Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Germany
| | - Janina Schoen
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Wolfgang Schuh
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Thomas Schüler
- Institute of Molecular and Clinical Immunology, Otto-von-Guericke University, Magdeburg, Germany
| | - Axel R. Schulz
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Sebastian Schulz
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Julia Schulze
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Sonia Simonetti
- Institute of Molecular Biology and Pathology, National Research Council of Italy (CNR), Rome, Italy
| | - Jeeshan Singh
- Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Medicine 3 – Rheumatology and Immunology and Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Katarzyna M. Sitnik
- Department of Viral Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Regina Stark
- Charité Universitätsmedizin Berlin – BIH Center for Regenerative Therapies, Berlin, Germany
- Sanquin Research – Adaptive Immunity, Amsterdam, The Netherlands
| | - Sarah Starossom
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christina Stehle
- Innate Immunity, German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Gastroenterology, Infectious Diseases, Rheumatology, Berlin, Germany
| | - Franziska Szelinski
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Leonard Tan
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore
- Department of Microbiology & Immunology, Immunology Programme, Life Science Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Attila Tarnok
- Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, Leipzig, Germany
- Department of Precision Instrument, Tsinghua University, Beijing, China
- Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
| | - Julia Tornack
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
| | - Timothy I. M. Tree
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
| | - Jasper J. P. van Beek
- Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Willem van de Veen
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland
| | | | - Chiara Vasco
- Istituto Nazionale di Genetica Molecolare Romeo ed Enrica Invernizzi (INGM), Milan, Italy
| | - Nikita A. Verheyden
- Institute for Molecular Medicine, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Anouk von Borstel
- Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
| | - Kirsten A. Ward-Hartstonge
- Department of Surgery, The University of British Columbia, Vancouver, Canada
- BC Children’s Hospital Research Institute, Vancouver, Canada
| | - Klaus Warnatz
- Department of Rheumatology and Clinical Immunology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Claudia Waskow
- Immunology of Aging, Leibniz Institute on Aging – Fritz Lipmann Institute, Jena, Germany
- Institute of Biochemistry and Biophysics, Faculty of Biological Sciences, Friedrich-Schiller-University Jena, Jena, Germany
- Department of Medicine III, Technical University Dresden, Dresden, Germany
| | - Annika Wiedemann
- German Rheumatism Research Center Berlin (DRFZ), Berlin, Germany
- Department of Medicine/Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Anneke Wilharm
- Institute of Immunology, Hannover Medical School, Hannover, Germany
| | - James Wing
- Immunology Frontier Research Center, Osaka University, Japan
| | - Oliver Wirz
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jens Wittner
- Division of Molecular Immunology, Nikolaus-Fiebiger-Center, Department of Internal Medicine III, University of Erlangen-Nürnberg, Erlangen, Germany
| | - Jennie H. M. Yang
- Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, UK
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC), Guy’s and St Thomas’ NHS Foundation Trust and King’s College London, London, UK
| | - Juhao Yang
- Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
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