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Subbiahanadar Chelladurai K, Selvan Christyraj JD, Rajagopalan K, Vadivelu K, Chandrasekar M, Das P, Kalimuthu K, Balamurugan N, Subramanian V, Selvan Christyraj JRS. Ex vivo functional whole organ in biomedical research: a review. J Artif Organs 2025; 28:131-145. [PMID: 39592544 DOI: 10.1007/s10047-024-01478-4] [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: 02/07/2024] [Accepted: 07/29/2024] [Indexed: 11/28/2024]
Abstract
Model systems are critical in biomedical and preclinical research. Animal and in vitro models serve an important role in our current understanding of human physiology, disease pathophysiology, and therapy development. However, if the system is between cell culture and animal models, it may be able to overcome the knowledge gap that exists in the current system. Studies employing ex vivo organs as models have not been thoroughly investigated. Though the integration of other organs and systems has an impact on many biological mechanisms and disorders, it can add a new dimension to modeling and aid in the identification of new possible therapeutic targets. Here, we have discussed why the ex vivo organ model is desirable and the importance of the inclusion of organs from diverse species, described its historical aspects, studied organs as models in scientific research, and its ex vivo stability. We also discussed, how an ex vivo organ model might help researchers better understand organ physiology, as well as organ-specific diseases and therapeutic targets. We emphasized how this ex vivo organ dynamics will be more competent than existing models, as well as what tissues or organs would have potentially viable longevity for ex vivo modeling including human tissues, organs, and/or at least biopsies and its possible advantage in clinical medicine including organ transplantation procedure and precision medicine.
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Affiliation(s)
- Karthikeyan Subbiahanadar Chelladurai
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
- School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN, 47907, USA
| | - Jackson Durairaj Selvan Christyraj
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India.
| | - Kamarajan Rajagopalan
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Kayalvizhi Vadivelu
- Department of Biotechnology, Bharathidasan University, Tiruchirappalli, Tamil Nadu, India
| | - Meikandan Chandrasekar
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Puja Das
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Kalishwaralal Kalimuthu
- Rajiv Gandhi Centre for Biotechnology, Department of Biotechnology, Thiruvananthapuram, Kerala, India
| | - Nivedha Balamurugan
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Vijayalakshmi Subramanian
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India
| | - Johnson Retnaraj Samuel Selvan Christyraj
- Molecular Biology and Stem Cell Research Lab, Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science & Technology, Chennai, Tamil Nadu, India.
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2
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Xu Y, Lee MK, de Weerd NA, Fu Z, Bertuzzo Veiga C, Dragoljevic D, Sviridov D, Hertzog PJ, Fleetwood AJ, Murphy AJ. Type I interferon signaling controls the early hematopoietic expansion in response to β-glucan. iScience 2025; 28:112347. [PMID: 40276764 PMCID: PMC12020881 DOI: 10.1016/j.isci.2025.112347] [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: 09/26/2024] [Revised: 12/02/2024] [Accepted: 03/31/2025] [Indexed: 04/26/2025] Open
Abstract
Rapid hematopoietic adaptations are important for building and sustaining the biological response to β-glucan. The signals involved in these early events have not yet been fully explored. Given that type I interferons are produced in response to β-glucan and can profoundly impact hematopoietic stem cell (HSC) function, we hypothesized that this pathway may be involved in the early bone marrow response to β-glucan. In vivo administration of β-glucan led to local interferon-α production in the peritoneal cavity and bone marrow, upregulation of its receptor, IFNAR1, specifically on long-term hematopoietic stem cells (LT-HSCs), and broad expansion of downstream progenitor subpopulations. We demonstrate that intact type I interferon signaling is critical for β-glucan-mediated LT-HSC proliferation, mitochondrial activity, and glycolytic commitment. By determining that type I interferon signaling is important for LT-HSCs, which sit at the apex of the hematopoietic hierarchy, we uncover an important component of the early inflammatory response to β-glucan.
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Affiliation(s)
- Yangsong Xu
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Man K.S. Lee
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Nicole A. de Weerd
- Centre for Innate Immunity and Infectious Diseases, Department of Molecular and Translational Science, Hudson Institute of Medical Research and Monash University, Clayton, VIC, Australia
| | - Ziyue Fu
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Camilla Bertuzzo Veiga
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Dragana Dragoljevic
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Dmitri Sviridov
- Lipoproteins and Atherosclerosis, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Paul J. Hertzog
- Centre for Innate Immunity and Infectious Diseases, Department of Molecular and Translational Science, Hudson Institute of Medical Research and Monash University, Clayton, VIC, Australia
| | - Andrew J. Fleetwood
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
| | - Andrew J. Murphy
- Haematopoiesis and Leukocyte Biology, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
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3
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Sabatier P, Lechner M, Guzmán UH, Beusch CM, Zeng X, Wang L, Izaguirre F, Seth A, Gritsenko O, Rodin S, Grinnemo KH, Ye Z, Olsen JV. Global analysis of protein turnover dynamics in single cells. Cell 2025; 188:2433-2450.e21. [PMID: 40168994 DOI: 10.1016/j.cell.2025.03.002] [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: 07/04/2024] [Revised: 12/20/2024] [Accepted: 03/03/2025] [Indexed: 04/03/2025]
Abstract
Single-cell proteomics (SCPs) has advanced significantly, yet it remains largely unidimensional, focusing primarily on protein abundances. In this study, we employed a pulsed stable isotope labeling by amino acids in cell culture (pSILAC) approach to simultaneously analyze protein abundance and turnover in single cells (SC-pSILAC). Using a state-of-the-art SCP workflow, we demonstrated that two SILAC labels are detectable from ∼4,000 proteins in single HeLa cells recapitulating known biology. We performed a large-scale time-series SC-pSILAC analysis of undirected differentiation of human induced pluripotent stem cells (iPSCs) encompassing 6 sampling times over 2 months and analyzed >1,000 cells. Protein turnover dynamics highlighted differentiation-specific co-regulation of protein complexes with core histone turnover, discriminating dividing and non-dividing cells. Lastly, correlating cell diameter with the abundance of individual proteins showed that histones and some cell-cycle proteins do not scale with cell size. The SC-pSILAC method provides a multidimensional view of protein dynamics in single-cell biology.
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Affiliation(s)
- Pierre Sabatier
- Novo Nordisk Foundation Center for Protein Research, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Cardio-Thoracic Translational Medicine (CTTM) Lab, Department of Surgical Sciences, Uppsala University, 752 37 Uppsala, Sweden.
| | - Maico Lechner
- Novo Nordisk Foundation Center for Protein Research, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Ulises H Guzmán
- Novo Nordisk Foundation Center for Protein Research, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Christian M Beusch
- Cardio-Thoracic Translational Medicine (CTTM) Lab, Department of Surgical Sciences, Uppsala University, 752 37 Uppsala, Sweden; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA
| | - Xinlei Zeng
- State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China
| | - Longteng Wang
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | | | - Anjali Seth
- Cellenion SASU, 60F Avenue Rockefeller, 69008 Lyon, France
| | - Olga Gritsenko
- Cardio-Thoracic Translational Medicine (CTTM) Lab, Department of Surgical Sciences, Uppsala University, 752 37 Uppsala, Sweden
| | - Sergey Rodin
- Cardio-Thoracic Translational Medicine (CTTM) Lab, Department of Surgical Sciences, Uppsala University, 752 37 Uppsala, Sweden
| | - Karl-Henrik Grinnemo
- Cardio-Thoracic Translational Medicine (CTTM) Lab, Department of Surgical Sciences, Uppsala University, 752 37 Uppsala, Sweden
| | - Zilu Ye
- Novo Nordisk Foundation Center for Protein Research, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China.
| | - Jesper V Olsen
- Novo Nordisk Foundation Center for Protein Research, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
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Zhang J, Zhong C, Chen L, Luo Y, Tang L, Yang J, Jia J, Xie X, Liu P, Yu J, Cui Y. Bletilla striata polysaccharide-mediated trained immunity drives the hematopoietic progenitors' expansion and myelopoiesis. Int Immunopharmacol 2025; 146:113909. [PMID: 39721454 DOI: 10.1016/j.intimp.2024.113909] [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: 10/04/2024] [Revised: 12/06/2024] [Accepted: 12/17/2024] [Indexed: 12/28/2024]
Abstract
Trained immunity represents a functional state of the innate immune response, characterized by enduring epigenetic reprogramming of innate immune cells. This phenomenon facilitates a sustained and advantageous reaction of myeloid cells to subsequent challenges. Bletilla striata polysaccharide (BSP) is the primary active component of Bletilla striata, mainly consisting of mannose and glucose in its chemical structure. Previous studies have demonstrated BSP's immunomodulatory properties, highlighting its effectiveness in enhancing the immune response. In the present study, we demonstrated that BSP administration induced the trained innate immunity, as evidenced by the BSP-induced generation of mature myeloid cells, especially neutrophils in the peripheral circulation in amouse model of chemotherapy-induced myelosuppression. Furthermore, we showed that BSP-induced trained immunity acts at the level of hematopoietic stem and progenitor cells (HSPCs) and induces the expansion of HSPCs. Mechanistically, our study demonstrated that BSP induced the activation of Notch signaling in HSPCs, and Notch signaling is indispensable for the BSP-mediated generation of trained HSPCs. Collectively, our data demonstrated for the first time that BSP induced trained immunity by regulating theexpansion of the myeloid progenitors. Harnessing trained immunity could be a promising strategy for protection from chemotherapy-induced myelosuppression.
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Affiliation(s)
- Jiangtao Zhang
- Centre for Translational Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China; Jiangxi Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Vascular Remodeling Diseases, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Chao Zhong
- Centre for Translational Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China; Jiangxi Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Vascular Remodeling Diseases, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Lanying Chen
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herb Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Yingying Luo
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herb Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China; Department of Cardiovascular Sciences and Centre for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Le Tang
- Centre for Translational Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China; Jiangxi Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Vascular Remodeling Diseases, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Jing Yang
- Centre for Translational Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China; Jiangxi Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Vascular Remodeling Diseases, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Jing Jia
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herb Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Xinxu Xie
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herb Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Peng Liu
- National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herb Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China
| | - Jun Yu
- Department of Cardiovascular Sciences and Centre for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Yaru Cui
- Jiangxi Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Vascular Remodeling Diseases, Jiangxi University of Chinese Medicine, Nanchang 330006, China; National Pharmaceutical Engineering Center for Solid Preparation of Chinese Herb Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China; Department of Cardiovascular Sciences and Centre for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
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5
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Watt SM, Roubelakis MG. Deciphering the Complexities of Adult Human Steady State and Stress-Induced Hematopoiesis: Progress and Challenges. Int J Mol Sci 2025; 26:671. [PMID: 39859383 PMCID: PMC11766050 DOI: 10.3390/ijms26020671] [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: 09/25/2024] [Revised: 01/05/2025] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
Human hematopoietic stem cells (HSCs) have traditionally been viewed as self-renewing, multipotent cells with enormous potential in sustaining essential steady state blood and immune cell production throughout life. Indeed, around 86% (1011-1012) of new cells generated daily in a healthy young human adult are of hematopoietic origin. Therapeutically, human HSCs have contributed to over 1.5 million hematopoietic cell transplants (HCTs) globally, making this the most successful regenerative therapy to date. We will commence this review by briefly highlighting selected key achievements (from 1868 to the end of the 20th century) that have contributed to this accomplishment. Much of our knowledge of hematopoiesis is based on small animal models that, despite their enormous importance, do not always recapitulate human hematopoiesis. Given this, we will critically review the progress and challenges faced in identifying adult human HSCs and tracing their lineage differentiation trajectories, referring to murine studies as needed. Moving forward and given that human hematopoiesis is dynamic and can readily adjust to a variety of stressors, we will then discuss recent research advances contributing to understanding (i) which HSPCs maintain daily steady state human hematopoiesis, (ii) where these are located, and (iii) which mechanisms come into play when homeostatic hematopoiesis switches to stress-induced or emergency hematopoiesis.
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Affiliation(s)
- Suzanne M. Watt
- Stem Cell Research, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9BQ, UK
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, North Terrace, Adelaide 5005, Australia
- Cancer Program, Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide 5001, Australia
| | - Maria G. Roubelakis
- Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens (NKUA), 11527 Athens, Greece;
- Cell and Gene Therapy Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), 11527 Athens, Greece
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6
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Niibori-Nambu A, Wang CQ, Chin DWL, Chooi JY, Hosoi H, Sonoki T, Tham CY, Nah GSS, Cirovic B, Tan DQ, Takizawa H, Sashida G, Goh Y, Tng J, Fam WN, Fullwood MJ, Suda T, Yang H, Tergaonkar V, Taniuchi I, Li S, Chng WJ, Osato M. Integrin-α9 overexpression underlies the niche-independent maintenance of leukemia stem cells in acute myeloid leukemia. Gene 2024; 928:148761. [PMID: 39002785 DOI: 10.1016/j.gene.2024.148761] [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: 04/13/2024] [Revised: 06/16/2024] [Accepted: 07/10/2024] [Indexed: 07/15/2024]
Abstract
Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble ligand, osteopontin (OPN). Retroviral insertional mutagenesis conducted on leukemia-prone Runx-deficient mice identified Itga9 OE as a novel leukemogenic event. Itga9 OE activates Akt and p38MAPK signaling pathways. The elevated Myc expression subsequently enhances ribosomal biogenesis to overcome the cell integrity defect caused by the preexisting Runx alteration. The Itga9-Myc axis, originally discovered in mice, was further confirmed in multiple human acute myeloid leukemia (AML) subtypes, other than RUNX leukemias. In addition, ITGA9 was shown to be a functional LSC marker of the best prognostic value among 14 known LSC markers tested. Notably, the binding of ITGA9 with soluble OPN, a known negative regulator against HSC activation, induced LSC dormancy, while the disruption of ITGA9-soluble OPN interaction caused rapid cell propagation. These findings suggest that the ITGA9 OE increases both actively proliferating leukemia cells and dormant LSCs in a well-balanced manner, thereby maintaining LSCs. The ITGA9 OE would serve as a novel therapeutic target in AML.
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Affiliation(s)
- Akiko Niibori-Nambu
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Chelsia Qiuxia Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Desmond Wai Loon Chin
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Jing Yuan Chooi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Hiroki Hosoi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Takashi Sonoki
- Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan
| | - Cheng-Yong Tham
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Giselle Sek Suan Nah
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Branko Cirovic
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Darren Qiancheng Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Hitoshi Takizawa
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Goro Sashida
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yufen Goh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Jiaqi Tng
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Wee Nih Fam
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Melissa Jane Fullwood
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Toshio Suda
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan; Institute of Hematology, Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Henry Yang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Vinay Tergaonkar
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Republic of Singapore
| | - Ichiro Taniuchi
- Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Shang Li
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore
| | - Wee Joo Chng
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; National University Cancer Institute, Singapore; National University Health System, Singapore.
| | - Motomi Osato
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of General Internal Medicine, Kumamoto Kenhoku Hospital, Kumamoto, Japan.
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Popravko A, Mackintosh L, Dzierzak E. A life-time of hematopoietic cell function: ascent, stability, and decline. FEBS Lett 2024; 598:2755-2764. [PMID: 38439688 PMCID: PMC11586595 DOI: 10.1002/1873-3468.14843] [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: 12/18/2023] [Revised: 02/02/2024] [Accepted: 02/15/2024] [Indexed: 03/06/2024]
Abstract
Aging is a set of complex processes that occur temporally and continuously. It is generally a unidirectional progression of cellular and molecular changes occurring during the life stages of cells, tissues and ultimately the whole organism. In vertebrate organisms, this begins at conception from the first steps in blastocyst formation, gastrulation, germ layer differentiation, and organogenesis to a continuum of embryonic, fetal, adolescent, adult, and geriatric stages. Tales of the "fountain of youth" and songs of being "forever young" are dominant ideas informing us that growing old is something science should strive to counteract. Here, we discuss the normal life stages of the blood system, particularly the historical recognition of its importance in the early growth stages of vertebrates, and what this means with respect to progressive gain and loss of hematopoietic function in the adult.
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Affiliation(s)
- Anna Popravko
- Institute for Regeneration and RepairUniversity of EdinburghUK
| | | | - Elaine Dzierzak
- Institute for Regeneration and RepairUniversity of EdinburghUK
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8
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Kapadia CD, Williams N, Dawson KJ, Watson C, Yousefzadeh MJ, Le D, Nyamondo K, Cagan A, Waldvogel S, De La Fuente J, Leongamornlert D, Mitchell E, Florez MA, Aguilar R, Martell A, Guzman A, Harrison D, Niedernhofer LJ, King KY, Campbell PJ, Blundell J, Goodell MA, Nangalia J. Clonal dynamics and somatic evolution of haematopoiesis in mouse. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.17.613129. [PMID: 39345649 PMCID: PMC11429886 DOI: 10.1101/2024.09.17.613129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Haematopoietic stem cells maintain blood production throughout life. While extensively characterised using the laboratory mouse, little is known about how the population is sustained and evolves with age. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1845 single cell-derived colonies, and used phylogenetic analysis to infer the ontogeny and population dynamics of the stem cell pool. Mouse stem cells and progenitors accrue ~45 somatic mutations per year, a rate only about 2-fold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns reveal that stem and multipotent progenitor cell pools are both established during embryogenesis, after which they independently self-renew in parallel over life. The stem cell pool grows steadily over the mouse lifespan to approximately 70,000 cells, self-renewing about every six weeks. Aged mice did not display the profound loss of stem cell clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing revealed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations and exhibited a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse.
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Affiliation(s)
- Chiraag D. Kapadia
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
| | | | - Kevin J. Dawson
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
| | - Caroline Watson
- Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Matthew J. Yousefzadeh
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
- Columbia Center for Translational Immunology, Columbia Center for Human Longevity, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - Duy Le
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
- Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA
| | - Kudzai Nyamondo
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge, UK
| | - Alex Cagan
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- Departments of Genetics, Pathology & Veterinary Medicine, University of Cambridge, Cambridge, UK
| | - Sarah Waldvogel
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
| | - Josephine De La Fuente
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
| | | | - Emily Mitchell
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
| | - Marcus A. Florez
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
- Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA
| | - Rogelio Aguilar
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
| | - Alejandra Martell
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
| | - Anna Guzman
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
| | | | - Laura J. Niedernhofer
- Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA
| | - Katherine Y. King
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
- Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA
| | | | - Jamie Blundell
- Early Cancer Institute, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
| | - Margaret A. Goodell
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA
| | - Jyoti Nangalia
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
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9
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Thompson Z, Anderson GA, Hernandez M, Alfaro Quinde C, Marchione A, Rodriguez M, Gabriel S, Binder V, Taylor AM, Kathrein KL. Ing4-deficiency promotes a quiescent yet transcriptionally poised state in hematopoietic stem cells. iScience 2024; 27:110521. [PMID: 39175773 PMCID: PMC11340613 DOI: 10.1016/j.isci.2024.110521] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/14/2024] [Accepted: 07/12/2024] [Indexed: 08/24/2024] Open
Abstract
Defining the mechanisms that regulate stem cell maintenance, proliferation, and differentiation is critical for identifying therapies for improving stem cell function under stress. Here, we have identified the tumor suppressor, inhibitor of growth 4 (Ing4), as a critical regulator of hematopoietic stem cell (HSC) homeostasis. Cancer cell line models with Ing4 deficiency have shown that Ing4 functions as a tumor suppressor, in part, due to Ing4-mediated regulation of several major signaling pathways, including c-Myc. In HSCs, we show Ing4 deficiency promotes gene expression signatures associated with activation, yet HSCs are arrested in G0, expressing several markers of quiescence. Functionally, Ing4-deficient HSCs demonstrate robust regenerative capacity following transplantation. Our findings suggest Ing4 deficiency promotes a poised state in HSCs, where they appear transcriptionally primed for activation but remain in a resting state. Our model provides key tools for further identification and characterization of pathways that control quiescence and self-renewal in HSCs.
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Affiliation(s)
- Zanshé Thompson
- University of South Carolina, Department of Biomedical Engineering, Columbia, SC, USA
| | - Georgina A. Anderson
- University of South Carolina, Department of Biological Sciences, Columbia, SC, USA
| | - Marco Hernandez
- University of South Carolina, Department of Biological Sciences, Columbia, SC, USA
| | - Carlos Alfaro Quinde
- University of South Carolina, Department of Biological Sciences, Columbia, SC, USA
| | - Alissa Marchione
- University of South Carolina, Department of Biological Sciences, Columbia, SC, USA
| | - Melanie Rodriguez
- University of South Carolina, Department of Biological Sciences, Columbia, SC, USA
| | - Seth Gabriel
- University of South Carolina, Department of Biological Sciences, Columbia, SC, USA
| | - Vera Binder
- Department of Hematology and Oncology, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians University, 80539 Munich, Germany
| | - Alison M. Taylor
- Columbia University Medical Center, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, New York, NY 10032, USA
| | - Katie L. Kathrein
- University of South Carolina, Department of Biological Sciences, Columbia, SC, USA
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10
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Caiado F, Manz MG. IL-1 in aging and pathologies of hematopoietic stem cells. Blood 2024; 144:368-377. [PMID: 38781562 DOI: 10.1182/blood.2023023105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/01/2024] [Accepted: 05/13/2024] [Indexed: 05/25/2024] Open
Abstract
ABSTRACT Defense-oriented inflammatory reactivity supports survival at younger age but might contribute to health impairments in modern, aging societies. The interleukin-1 (IL-1) cytokines are highly conserved and regulated, pleiotropic mediators of inflammation, essential to respond adequately to infection and tissue damage but also with potential host damaging effects when left unresolved. In this review, we discuss how continuous low-level IL-1 signaling contributes to aging-associated hematopoietic stem and progenitor cell (HSPC) functional impairments and how this inflammatory selective pressure acts as a driver of more profound hematological alterations, such as clonal hematopoiesis of indeterminate potential, and to overt HSPC diseases, like myeloproliferative and myelodysplastic neoplasia as well as acute myeloid leukemia. Based on this, we outline how IL-1 pathway inhibition might be used to prevent or treat inflammaging-associated HSPC pathologies.
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Affiliation(s)
- Francisco Caiado
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich, Zurich, Switzerland
| | - Markus G Manz
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich, Zurich, Switzerland
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11
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Belmonte M, Cabrera-Cosme L, Øbro NF, Li J, Grinfeld J, Milek J, Bennett E, Irvine M, Shepherd MS, Cull AH, Boyd G, Riedel LM, Chi Che JL, Oedekoven CA, Baxter EJ, Green AR, Barlow JL, Kent DG. Increased CXCL10 (IP-10) is associated with advanced myeloproliferative neoplasms and its loss dampens erythrocytosis in mouse models. Exp Hematol 2024; 135:104246. [PMID: 38763471 DOI: 10.1016/j.exphem.2024.104246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 05/04/2024] [Accepted: 05/15/2024] [Indexed: 05/21/2024]
Abstract
Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of the disease, but the precise role of the cellular microenvironment in disease initiation and evolution remains poorly understood. In myeloproliferative neoplasms (MPNs), higher levels of specific cytokines have been previously correlated with increased disease severity (tumor necrosis factor-alpha [TNF-α], interferon gamma-induced protein-10 [IP-10 or CXCL10]) and decreased survival (interleukin 8 [IL-8]). Whereas TNF-α and IL-8 have been studied by numerous groups, there is a relative paucity of studies on IP-10 (CXCL10). Here we explore the relationship of IP-10 levels with detailed genomic and clinical data and undertake a complementary cytokine screen alongside functional assays in a wide range of MPN mouse models. Similar to patients, levels of IP-10 were increased in mice with more severe disease phenotypes (e.g., JAK2V617F/V617F TET2-/- double-mutant mice) compared with those with less severe phenotypes (e.g., CALRdel52 or JAK2+/V617F mice) and wild-type (WT) littermate controls. Although exposure to IP-10 did not directly alter proliferation or survival in single hematopoietic stem cells (HSCs) in vitro, IP-10-/- mice transplanted with disease-initiating HSCs developed an MPN phenotype more slowly, suggesting that the effect of IP-10 loss was noncell-autonomous. To explore the broader effects of IP-10 loss, we crossed IP-10-/- mice into a series of MPN mouse models and showed that its loss reduces the erythrocytosis observed in mice with the most severe phenotype. Together, these data point to a potential role for blocking IP-10 activity in the management of MPNs.
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Affiliation(s)
- Miriam Belmonte
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Lilia Cabrera-Cosme
- Department of Biology, Centre for Blood Research, York Biomedical Research Institute, University of York, York, United Kingdom
| | - Nina F Øbro
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Juan Li
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Jacob Grinfeld
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, United Kingdom
| | - Joanna Milek
- Department of Biology, Centre for Blood Research, York Biomedical Research Institute, University of York, York, United Kingdom
| | - Ellie Bennett
- Department of Biology, Centre for Blood Research, York Biomedical Research Institute, University of York, York, United Kingdom
| | - Melissa Irvine
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Mairi S Shepherd
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - Alyssa H Cull
- Department of Biology, Centre for Blood Research, York Biomedical Research Institute, University of York, York, United Kingdom
| | - Grace Boyd
- Department of Biology, Centre for Blood Research, York Biomedical Research Institute, University of York, York, United Kingdom
| | - Lisa M Riedel
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - James Lok Chi Che
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom; Department of Biology, Centre for Blood Research, York Biomedical Research Institute, University of York, York, United Kingdom
| | - Caroline A Oedekoven
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom
| | - E Joanna Baxter
- Department of Haematology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, United Kingdom
| | - Anthony R Green
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, United Kingdom
| | - Jillian L Barlow
- Department of Biology, Centre for Blood Research, York Biomedical Research Institute, University of York, York, United Kingdom
| | - David G Kent
- Wellcome Medical Research Council (MRC) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom; Department of Haematology, University of Cambridge, Cambridge, United Kingdom; Department of Biology, Centre for Blood Research, York Biomedical Research Institute, University of York, York, United Kingdom.
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12
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Yahagi A, Mochizuki-Kashio M, Sorimachi Y, Takubo K, Nakamura-Ishizu A. Abcb10 regulates murine hematopoietic stem cell potential and erythroid differentiation. Exp Hematol 2024; 135:104191. [PMID: 38493949 DOI: 10.1016/j.exphem.2024.104191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 02/12/2024] [Accepted: 02/14/2024] [Indexed: 03/19/2024]
Abstract
Erythropoiesis in the adult bone marrow relies on mitochondrial membrane transporters to facilitate heme and hemoglobin production. Erythrocytes in the bone marrow are produced although the differentiation of erythroid progenitor cells that originate from hematopoietic stem cells (HSCs). Whether and how mitochondria transporters potentiate HSCs and affect their differentiation toward erythroid lineage remains unclear. Here, we show that the ATP-binding cassette (ABC) transporter 10 (Abcb10), located on the inner mitochondrial membrane, is essential for HSC maintenance and erythroid-lineage differentiation. Induced deletion of Abcb10 in adult mice significantly increased erythroid progenitor cell and decreased HSC number within the bone marrow (BM). Functionally, Abcb10-deficient HSCs exhibited significant decreases in stem cell potential but with a skew toward erythroid-lineage differentiation. Mechanistically, deletion of Abcb10 rendered HSCs with excess mitochondrial iron accumulation and oxidative stress yet without alteration in mitochondrial bioenergetic function. However, impaired hematopoiesis could not be rescued through the in vivo administration of a mitochondrial iron chelator or antioxidant to Abcb10-deficient mice. Abcb10-mediated mitochondrial iron transfer is thus pivotal for the regulation of physiologic HSC potential and erythroid-lineage differentiation.
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Affiliation(s)
- Ayano Yahagi
- Department of Microscopic and Developmental Anatomy, Tokyo Women's Medical University, Tokyo, Japan
| | - Makiko Mochizuki-Kashio
- Department of Microscopic and Developmental Anatomy, Tokyo Women's Medical University, Tokyo, Japan
| | - Yuriko Sorimachi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Keiyo Takubo
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Ayako Nakamura-Ishizu
- Department of Microscopic and Developmental Anatomy, Tokyo Women's Medical University, Tokyo, Japan.
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13
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Filia A, Mitroulis I, Loukogiannaki C, Grigoriou M, Banos A, Sentis G, Giannouli S, Karali V, Athanasiadis E, Kokkinopoulos I, Boumpas DT. Single-cell transcriptomic analysis of hematopoietic progenitor cells from patients with systemic lupus erythematosus reveals interferon-inducible reprogramming in early progenitors. Front Immunol 2024; 15:1383358. [PMID: 38779657 PMCID: PMC11109438 DOI: 10.3389/fimmu.2024.1383358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/18/2024] [Indexed: 05/25/2024] Open
Abstract
Introduction Immune cells that contribute to the pathogenesis of systemic lupus erythematosus (SLE) derive from adult hematopoietic stem and progenitor cells (HSPCs) within the bone marrow (BM). For this reason, we reasoned that fundamental abnormalities in SLE can be traced to a BM-derived HSPC inflammatory signature. Methods BM samples from four SLE patients, six healthy controls, and two umbilical cord blood (CB) samples were used. CD34+ cells were isolated from BM and CB samples, and single-cell RNA-sequencing was performed. Results A total of 426 cells and 24,473 genes were used in the analysis. Clustering analysis resulted in seven distinct clusters of cell types. Mutually exclusive markers, which were characteristic of each cell type, were identified. We identified three HSPC subpopulations, one of which consisted of proliferating cells (MKI67 expressing cells), one T-like, one B-like, and two myeloid-like progenitor subpopulations. Differential expression analysis revealed i) cell cycle-associated signatures, in healthy BM of HSPC clusters 3 and 4 when compared with CB, and ii) interferon (IFN) signatures in SLE BM of HSPC clusters 3 and 4 and myeloid-like progenitor cluster 5 when compared with healthy controls. The IFN signature in SLE appeared to be deregulated following TF regulatory network analysis and differential alternative splicing analysis between SLE and healthy controls in HSPC subpopulations. Discussion This study revealed both quantitative-as evidenced by decreased numbers of non-proliferating early progenitors-and qualitative differences-characterized by an IFN signature in SLE, which is known to drive loss of function and depletion of HSPCs. Chronic IFN exposure affects early hematopoietic progenitors in SLE, which may account for the immune aberrancies and the cytopenias in SLE.
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Affiliation(s)
- Anastasia Filia
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Ioannis Mitroulis
- 1st Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Catherine Loukogiannaki
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Maria Grigoriou
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
- 1st Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis, Greece
| | - Aggelos Banos
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - George Sentis
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Stavroula Giannouli
- 2nd Department of Internal Medicine, Ippokrateion Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Vassiliki Karali
- 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Emmanouil Athanasiadis
- Medical Image and Signal Processing Laboratory, Department of Biomedical Engineering, University of West Attica, Athens, Greece
| | - Ioannis Kokkinopoulos
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
| | - Dimitrios T. Boumpas
- Laboratory of Autoimmunity and Inflammation, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece
- 4th Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece
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14
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Bush SJ, Nikola R, Han S, Suzuki S, Yoshida S, Simons BD, Goriely A. Adult Human, but Not Rodent, Spermatogonial Stem Cells Retain States with a Foetal-like Signature. Cells 2024; 13:742. [PMID: 38727278 PMCID: PMC11083513 DOI: 10.3390/cells13090742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 04/17/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
Spermatogenesis involves a complex process of cellular differentiation maintained by spermatogonial stem cells (SSCs). Being critical to male reproduction, it is generally assumed that spermatogenesis starts and ends in equivalent transcriptional states in related species. Based on single-cell gene expression profiling, it has been proposed that undifferentiated human spermatogonia can be subclassified into four heterogenous subtypes, termed states 0, 0A, 0B, and 1. To increase the resolution of the undifferentiated compartment and trace the origin of the spermatogenic trajectory, we re-analysed the single-cell (sc) RNA-sequencing libraries of 34 post-pubescent human testes to generate an integrated atlas of germ cell differentiation. We then used this atlas to perform comparative analyses of the putative SSC transcriptome both across human development (using 28 foetal and pre-pubertal scRNA-seq libraries) and across species (including data from sheep, pig, buffalo, rhesus and cynomolgus macaque, rat, and mouse). Alongside its detailed characterisation, we show that the transcriptional heterogeneity of the undifferentiated spermatogonial cell compartment varies not only between species but across development. Our findings associate 'state 0B' with a suppressive transcriptomic programme that, in adult humans, acts to functionally oppose proliferation and maintain cells in a ready-to-react state. Consistent with this conclusion, we show that human foetal germ cells-which are mitotically arrested-can be characterised solely as state 0B. While germ cells with a state 0B signature are also present in foetal mice (and are likely conserved at this stage throughout mammals), they are not maintained into adulthood. We conjecture that in rodents, the foetal-like state 0B differentiates at birth into the renewing SSC population, whereas in humans it is maintained as a reserve population, supporting testicular homeostasis over a longer reproductive lifespan while reducing mutagenic load. Together, these results suggest that SSCs adopt differing evolutionary strategies across species to ensure fertility and genome integrity over vastly differing life histories and reproductive timeframes.
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Affiliation(s)
- Stephen J. Bush
- MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Rafail Nikola
- MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK
| | - Seungmin Han
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK
| | - Shinnosuke Suzuki
- Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan
- Graduate Institute for Advanced Studies, SOKENDAI, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan
| | - Shosei Yoshida
- Division of Germ Cell Biology, National Institute for Basic Biology, National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan
- Graduate Institute for Advanced Studies, SOKENDAI, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan
| | - Benjamin D. Simons
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK
- Wellcome—MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
- Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Science, University of Cambridge, Cambridge CB3 0WA, UK
| | - Anne Goriely
- MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK
- NIHR Biomedical Research Centre, Oxford OX3 7JX, UK
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15
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Saluja S, Bansal I, Bhardwaj R, Beg MS, Palanichamy JK. Inflammation as a driver of hematological malignancies. Front Oncol 2024; 14:1347402. [PMID: 38571491 PMCID: PMC10987768 DOI: 10.3389/fonc.2024.1347402] [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: 12/01/2023] [Accepted: 03/05/2024] [Indexed: 04/05/2024] Open
Abstract
Hematopoiesis is a tightly regulated process that produces all adult blood cells and immune cells from multipotent hematopoietic stem cells (HSCs). HSCs usually remain quiescent, and in the presence of external stimuli like infection or inflammation, they undergo division and differentiation as a compensatory mechanism. Normal hematopoiesis is impacted by systemic inflammation, which causes HSCs to transition from quiescence to emergency myelopoiesis. At the molecular level, inflammatory cytokine signaling molecules such as tumor necrosis factor (TNF), interferons, interleukins, and toll-like receptors can all cause HSCs to multiply directly. These cytokines actively encourage HSC activation, proliferation, and differentiation during inflammation, which results in the generation and activation of immune cells required to combat acute injury. The bone marrow niche provides numerous soluble and stromal cell signals, which are essential for maintaining normal homeostasis and output of the bone marrow cells. Inflammatory signals also impact this bone marrow microenvironment called the HSC niche to regulate the inflammatory-induced hematopoiesis. Continuous pro-inflammatory cytokine and chemokine activation can have detrimental effects on the hematopoietic system, which can lead to cancer development, HSC depletion, and bone marrow failure. Reactive oxygen species (ROS), which damage DNA and ultimately lead to the transformation of HSCs into cancerous cells, are produced due to chronic inflammation. The biological elements of the HSC niche produce pro-inflammatory cytokines that cause clonal growth and the development of leukemic stem cells (LSCs) in hematological malignancies. The processes underlying how inflammation affects hematological malignancies are still not fully understood. In this review, we emphasize the effects of inflammation on normal hematopoiesis, the part it plays in the development and progression of hematological malignancies, and potential therapeutic applications for targeting these pathways for therapy in hematological malignancies.
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16
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Kawahigashi T, Iwanami S, Takahashi M, Bhadury J, Iwami S, Yamazaki S. Age-related changes in the hematopoietic stem cell pool revealed via quantifying the balance of symmetric and asymmetric divisions. PLoS One 2024; 19:e0292575. [PMID: 38285676 PMCID: PMC10824414 DOI: 10.1371/journal.pone.0292575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 01/02/2024] [Indexed: 01/31/2024] Open
Abstract
Hematopoietic stem cells (HSCs) are somatic stem cells that continuously generate lifelong supply of blood cells through a balance of symmetric and asymmetric divisions. It is well established that the HSC pool increases with age. However, not much is known about the underlying cause for these observed changes. Here, using a novel method combining single-cell ex vivo HSC expansion with mathematical modeling, we quantify HSC division types (stem cell-stem cell (S-S) division, stem cell-progenitor cell (S-P) division, and progenitor cell-progenitor cell (P-P) division) as a function of the aging process. Our time-series experiments reveal how changes in these three modes of division can explain the increase in HSC numbers with age. Contrary to the popular notion that HSCs divide predominantly through S-P divisions, we show that S-S divisions are predominant throughout the lifespan of the animal, thereby expanding the HSC pool. We, therefore, provide a novel mathematical model-based experimental validation for reflecting HSC dynamics in vivo.
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Affiliation(s)
- Teiko Kawahigashi
- Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Shoya Iwanami
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
| | - Munetomo Takahashi
- Graduate School and Faculty of Medicine, The University of Tokyo, Tokyo, Japan
- Medical Research Council Toxicology Unit, Gleeson Building, Tennis Court Road, University of Cambridge, Cambridge, United Kingdom
| | - Joydeep Bhadury
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States of America
| | - Shingo Iwami
- interdisciplinary Biology Laboratory (iBLab), Division of Natural Science, Graduate School of Science, Nagoya University, Nagoya, Japan
- Institute of Mathematics for Industry, Kyushu University, Fukuoka, Japan
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
- Interdisciplinary Theoretical and Mathematical Sciences Program (iTHEMS), RIKEN, Saitama, Japan
- NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
- Science Groove Inc., Fukuoka, Japan
| | - Satoshi Yamazaki
- Division of Stem Cell Biology, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Laboratory of Stem Cell Therapy, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
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17
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Fregona V, Bayet M, Bouttier M, Largeaud L, Hamelle C, Jamrog LA, Prade N, Lagarde S, Hebrard S, Luquet I, Mansat-De Mas V, Nolla M, Pasquet M, Didier C, Khamlichi AA, Broccardo C, Delabesse É, Mancini SJ, Gerby B. Stem cell-like reprogramming is required for leukemia-initiating activity in B-ALL. J Exp Med 2024; 221:e20230279. [PMID: 37930337 PMCID: PMC10626194 DOI: 10.1084/jem.20230279] [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: 02/14/2023] [Revised: 08/31/2023] [Accepted: 10/03/2023] [Indexed: 11/07/2023] Open
Abstract
B cell acute lymphoblastic leukemia (B-ALL) is a multistep disease characterized by the hierarchical acquisition of genetic alterations. However, the question of how a primary oncogene reprograms stem cell-like properties in committed B cells and leads to a preneoplastic population remains unclear. Here, we used the PAX5::ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal, and the emergence of preleukemic stem cells (pre-LSCs). We show that PAX5::ELN disrupts the differentiation of preleukemic cells by enforcing the IL7r/JAK-STAT pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B cell identity and reactivate an immature molecular program, reminiscent of human B-ALL chemo-resistant cells. Finally, our transcriptional regulatory network reveals the transcription factor EGR1 as a strong candidate to control quiescence/resistance of PAX5::ELN pre-LSCs as well as of blasts from human B-ALL.
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Affiliation(s)
- Vincent Fregona
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
| | - Manon Bayet
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
| | - Mathieu Bouttier
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
| | - Laetitia Largeaud
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
- Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
- Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Camille Hamelle
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
| | - Laura A. Jamrog
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
| | - Naïs Prade
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
- Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
- Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Stéphanie Lagarde
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
- Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
- Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Sylvie Hebrard
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
| | - Isabelle Luquet
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
- Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
- Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Véronique Mansat-De Mas
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
- Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Marie Nolla
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
- Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Marlène Pasquet
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
- Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Christine Didier
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
| | - Ahmed Amine Khamlichi
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, Centre Nationale de la Recherche Scientifique, Université Toulouse III—Paul Sabatier (UT3), Toulouse, France
| | - Cyril Broccardo
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
| | - Éric Delabesse
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
- Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France
- Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Stéphane J.C. Mancini
- Université de Rennes, Etablissement Français du Sang, Inserm, MOBIDIC—UMR_S 1236, Rennes, France
| | - Bastien Gerby
- Université de Toulouse, Inserm, Centre Nationale de la Recherche Scientifique, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
- Equipe Labellisée Ligue Contre le Cancer 2023, Toulouse, France
- Équipe Labellisée Institut Carnot Opale, Toulouse, France
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18
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McClatchy J, Strogantsev R, Wolfe E, Lin HY, Mohammadhosseini M, Davis BA, Eden C, Goldman D, Fleming WH, Conley P, Wu G, Cimmino L, Mohammed H, Agarwal A. Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells. Nat Commun 2023; 14:8102. [PMID: 38062031 PMCID: PMC10703894 DOI: 10.1038/s41467-023-43697-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 11/16/2023] [Indexed: 12/18/2023] Open
Abstract
Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1β is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1β promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1β administration, which is resisted by Tet2-deficient HSPCs, and thus IL1β enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1β-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis.
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Affiliation(s)
- J McClatchy
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR, USA
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - R Strogantsev
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - E Wolfe
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR, USA
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - H Y Lin
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR, USA
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - M Mohammadhosseini
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR, USA
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - B A Davis
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR, USA
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - C Eden
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR, USA
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - D Goldman
- Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR, USA
- Division of Pediatric Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA
| | - W H Fleming
- Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR, USA
- Division of Pediatric Hematology and Oncology, Oregon Health & Science University, Portland, OR, USA
| | - P Conley
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA
| | - G Wu
- Department of Medical Informatics and Clinical Epidemiology, Oregon Health & Science University, Portland, OR, USA
| | - L Cimmino
- University of Miami, Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, Miami, USA
| | - H Mohammed
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - A Agarwal
- Division of Oncological Sciences, Oregon Health & Science University, Portland, OR, USA.
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR, USA.
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
- Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR, USA.
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
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19
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Song T, Yao Y, Papoin J, Sherry B, Diamond B, Gu H, Blanc L, Zou YR. Host factor TIMP1 sustains long-lasting myeloid-biased hematopoiesis after severe infection. J Exp Med 2023; 220:e20230018. [PMID: 37851372 PMCID: PMC10585121 DOI: 10.1084/jem.20230018] [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: 01/03/2023] [Revised: 07/10/2023] [Accepted: 10/03/2023] [Indexed: 10/19/2023] Open
Abstract
Infection is able to promote innate immunity by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, the mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. In post-infection mice, the tissue inhibitor of metalloproteinases 1 (TIMP1) is constitutively upregulated. TIMP1 antagonizes the function of ADAM10, an essential cleavage enzyme for the activation of the Notch signaling pathway, which suppresses myelopoiesis. While TIMP1 is dispensable for myelopoiesis under the steady state, increased TIMP1 enhances myelopoiesis after infection. Thus, our data establish TIMP1 as a molecular reporter of past infection in the host, sustaining hyper myelopoiesis and serving as a potential therapeutic target for modulating HSPC cell fate.
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Affiliation(s)
- Tengfei Song
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Yonghong Yao
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Julien Papoin
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Barbara Sherry
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA
| | - Betty Diamond
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA
| | - Hua Gu
- Laboratory of Molecular Immunology, Institut de Recherches Cliniques de Montréal, Montréal, Canada
| | - Lionel Blanc
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA
| | - Yong-Rui Zou
- Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
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20
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Cui Z, Wei H, Goding C, Cui R. Stem cell heterogeneity, plasticity, and regulation. Life Sci 2023; 334:122240. [PMID: 37925141 DOI: 10.1016/j.lfs.2023.122240] [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: 09/08/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 11/06/2023]
Abstract
As a population of homogeneous cells with both self-renewal and differentiation potential, stem cell pools are highly compartmentalized and contain distinct subsets that exhibit stable but limited heterogeneity during homeostasis. However, their striking plasticity is showcased under natural or artificial stress, such as injury, transplantation, cancer, and aging, leading to changes in their phenotype, constitution, metabolism, and function. The complex and diverse network of cell-extrinsic niches and signaling pathways, together with cell-intrinsic genetic and epigenetic regulators, tightly regulate both the heterogeneity during homeostasis and the plasticity under perturbation. Manipulating these factors offers better control of stem cell behavior and a potential revolution in the current state of regenerative medicine. However, disruptions of normal regulation by genetic mutation or excessive plasticity acquisition may contribute to the formation of tumors. By harnessing innovative techniques that enhance our understanding of stem cell heterogeneity and employing novel approaches to maximize the utilization of stem cell plasticity, stem cell therapy holds immense promise for revolutionizing the future of medicine.
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Affiliation(s)
- Ziyang Cui
- Department of Dermatology and Venerology, Peking University First Hospital, Beijing 100034, China.
| | - Hope Wei
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, United States of America
| | - Colin Goding
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX37DQ, UK
| | - Rutao Cui
- Skin Disease Research Institute, The 2nd Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
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21
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Zhan Q, Wang J, Zhang H, Zhang L. E3 ubiquitin ligase on the biological properties of hematopoietic stem cell. J Mol Med (Berl) 2023; 101:543-556. [PMID: 37081103 PMCID: PMC10163092 DOI: 10.1007/s00109-023-02315-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 02/25/2023] [Accepted: 03/30/2023] [Indexed: 04/22/2023]
Abstract
Hematopoietic stem cells are a group of heterogeneity cells with the potential to differentiate into various types of mature blood cells. Their basic biological properties include quiescence, self-renewal, multilineage differentiation, and homing ability, with the homing of exogenous hematopoietic stem cells after transplantation becoming a new focus, while the first three properties share some similarity in mechanism due to connectivity. In various complex mechanisms, the role of E3 ubiquitin ligases in hematopoietic homeostasis and malignant transformation is receiving increasing attention. As a unique part, E3 ubiquitin ligases play an important role in physiological regulation mechanism of posttranslational modification. In this review, we focus on the recent progress of the crucial role of E3 ubiquitin ligases that target specific proteins for ubiquitination to regulate biological properties of hematopoietic stem cells. Additionally, this paper deals with E3 ubiquitin ligases that affect the biological properties through aging and summarizes the relevant applications of targeting E3 ligases in hematopoietic malignancies. We present some ideas on the clinical application of E3 ubiquitin ligase to regulate hematopoietic stem cells and also believe that it is meaningful to study the upstream signal of these E3 ubiquitin ligases because hematopoietic stem cell dysfunction is caused by deficiency of some E3 ligases.
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Affiliation(s)
- Qianru Zhan
- Department of Hematology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, Liaoning, People's Republic of China
| | - Jing Wang
- Department of Hematology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, Liaoning, People's Republic of China
| | - Heyang Zhang
- Department of Hematology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, Liaoning, People's Republic of China.
| | - Lijun Zhang
- Department of Hematology, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, Liaoning, People's Republic of China.
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22
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Li F, Sun J. Differentiation Kinetics of Hematopoietic Stem and Progenitor Cells In Vivo Are Not Affected by β-Glucan Treatment in Trained Immunity. Inflammation 2023; 46:718-729. [PMID: 36414879 DOI: 10.1007/s10753-022-01767-1] [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: 10/12/2022] [Revised: 11/08/2022] [Accepted: 11/13/2022] [Indexed: 11/24/2022]
Abstract
Agonists of trained immunity induce epigenetic changes in hematopoietic stem and progenitor cells (HSPCs) to generate long-lasting immune protection. Although trained HSPCs generate myeloid cells with increased responsiveness to secondary challenges, whether their differentiation kinetics is affected by prior exposure to inducers of trained immunity remains elusive. Here, we used lineage tracing to examine the cell fates of endothelial protein C receptor-positive hematopoietic stem cells (EPCR+ HSCs) and fms-like tyrosine kinase 3-positive multipotent progenitor cells (Flt3+ MPPs) in β-glucan-induced trained immunity. We found that although β-glucan triggered the expected expansion of myeloid progenitors, the differentiation behaviors of EPCR+ HSCs and Flt3+ MPPs in multiple cycles of hematopoietic regeneration were hardly affected. Thus, our results rule out changed kinetics in cell differentiation by EPCR+ HSC and Flt3+ MPP as the cause of enhanced myelopoiesis upon secondary immune challenges.
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Affiliation(s)
- Feiyang Li
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Jianlong Sun
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
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23
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Bukkuri A, Pienta KJ, Hockett I, Austin RH, Hammarlund EU, Amend SR, Brown JS. Modeling cancer's ecological and evolutionary dynamics. Med Oncol 2023; 40:109. [PMID: 36853375 PMCID: PMC9974726 DOI: 10.1007/s12032-023-01968-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 02/05/2023] [Indexed: 03/01/2023]
Abstract
In this didactic paper, we present a theoretical modeling framework, called the G-function, that integrates both the ecology and evolution of cancer to understand oncogenesis. The G-function has been used in evolutionary ecology, but has not been widely applied to problems in cancer. Here, we build the G-function framework from fundamental Darwinian principles and discuss how cancer can be seen through the lens of ecology, evolution, and game theory. We begin with a simple model of cancer growth and add on components of cancer cell competition and drug resistance. To aid in exploration of eco-evolutionary modeling with this approach, we also present a user-friendly software tool. By the end of this paper, we hope that readers will be able to construct basic G function models and grasp the usefulness of the framework to understand the games cancer plays in a biologically mechanistic fashion.
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Affiliation(s)
- Anuraag Bukkuri
- Cancer Biology and Evolution Program and Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, USA.
- Tissue Development and Evolution Research Group, Department of Laboratory Medicine, Lund University, Lund, Sweden.
| | - Kenneth J Pienta
- The Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, USA
| | - Ian Hockett
- The Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, USA
| | | | - Emma U Hammarlund
- Tissue Development and Evolution Research Group, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Sarah R Amend
- The Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, USA
| | - Joel S Brown
- Cancer Biology and Evolution Program and Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, USA
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24
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Zhong D, Jiang H, Zhou C, Ahmed A, Li H, Wei X, Lian Q, Tastemel M, Xin H, Ge M, Zhang C, Jing L. The microbiota regulates hematopoietic stem and progenitor cell development by mediating inflammatory signals in the niche. Cell Rep 2023; 42:112116. [PMID: 36795566 DOI: 10.1016/j.celrep.2023.112116] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 12/23/2022] [Accepted: 01/27/2023] [Indexed: 02/17/2023] Open
Abstract
The commensal microbiota regulates the self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) in bone marrow. Whether and how the microbiota influences HSPC development during embryogenesis is unclear. Using gnotobiotic zebrafish, we show that the microbiota is necessary for HSPC development and differentiation. Individual bacterial strains differentially affect HSPC formation, independent of their effects on myeloid cells. Early-life dysbiosis in chd8-/- zebrafish impairs HSPC development. Wild-type microbiota promote HSPC development by controlling basal inflammatory cytokine expression in kidney niche, and chd8-/- commensals elicit elevated inflammatory cytokines that reduce HSPCs and enhance myeloid differentiation. We identify an Aeromonas veronii strain with immuno-modulatory activities that fails to induce HSPC development in wild-type fish but selectively inhibits kidney cytokine expression and rebalances HSPC development in chd8-/- zebrafish. Our studies highlight the important roles of a balanced microbiome during early HSPC development that ensure proper establishment of lineal precursor for adult hematopoietic system.
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Affiliation(s)
- Dan Zhong
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Key Laboratory of Veterinary Biotechnology, Shanghai 200240, China
| | - Haowei Jiang
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Chengzhuo Zhou
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Abrar Ahmed
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Hongji Li
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xiaona Wei
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Qiuyu Lian
- UM-SJTU Joint Institute, Department of Automation, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Melodi Tastemel
- Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
| | - Hongyi Xin
- Global Institute of Future Technology, Department of Automation, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Mei Ge
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Laiyi Center for Biopharmaceutical R&D, Shanghai 200240, China
| | - Chenhong Zhang
- State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Lili Jing
- Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Key Laboratory of Veterinary Biotechnology, Shanghai 200240, China.
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25
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Understanding Hematopoietic Stem Cell Dynamics—Insights from Mathematical Modelling. CURRENT STEM CELL REPORTS 2023. [DOI: 10.1007/s40778-023-00224-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Abstract
Purpose of review
Hematopoietic stem cells (HSCs) drive blood-cell production (hematopoiesis). Out-competition of HSCs by malignant cells occurs in many hematologic malignancies like acute myeloid leukemia (AML). Through mathematical modelling, HSC dynamics and their impact on healthy blood cell formation can be studied, using mathematical analysis and computer simulations. We review important work within this field and discuss mathematical modelling as a tool for attaining biological insight.
Recent findings
Various mechanism-based models of HSC dynamics have been proposed in recent years. Key properties of such models agree with observations and medical knowledge and suggest relations between stem cell properties, e.g., rates of division and the temporal evolution of the HSC population. This has made it possible to study how HSC properties shape clinically relevant processes, including engraftment following an HSC transplantation and the response to different treatment.
Summary
Understanding how properties of HSCs affect hematopoiesis is important for efficient treatment of diseases. Mathematical modelling can contribute significantly to these efforts.
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26
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Perry JM. Immune System Influence on Hematopoietic Stem Cells and Leukemia Development. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1442:125-135. [PMID: 38228962 DOI: 10.1007/978-981-99-7471-9_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2024]
Abstract
Hematopoietic stem cells (HSCs) are the source for all blood cells, including immune cells, and they interact dynamically with the immune system. This chapter will explore the nature of stem cells, particularly HSCs, in the context of their immune microenvironment. The dynamic interactions between stem cells and the immune system can have profound implications for current and future therapies, particularly regarding a potential "immune-privileged" HSC microenvironment. Immune/stem cell interactions change during times of stress and injury. Recent advances in cancer immunotherapy have overturned the long-standing belief that, being derived from the self, cancer cells should be immunotolerant. Instead, an immunosurveillance system recognizes and eliminates emergent pre-cancerous cells. Only in the context of a failing immunosurveillance system does cancer fully develop. Combined with the knowledge that stem cells or their unique properties can be critically important for cancer initiation, persistence, and resistance to therapy, understanding the unique immune properties of stem cells will be critical for the development of future cancer therapies. Accordingly, the therapeutic implications for leukemic stem cells (LSCs) inheriting an immune-privileged state from HSCs will be discussed. Through their dynamic interactions with a diverse immune system, stem cells serve as the light and dark root of cancer prevention vs. development.
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Affiliation(s)
- John M Perry
- Children's Mercy Kansas City, Kansas City, MO, USA.
- University of Kansas Medical Center, Kansas City, KS, USA.
- University of Missouri Kansas City School of Medicine, Kansas City, MO, USA.
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27
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Shiroshita K, Kobayashi H, Watanuki S, Karigane D, Sorimachi Y, Fujita S, Tamaki S, Haraguchi M, Itokawa N, Aoyoama K, Koide S, Masamoto Y, Kobayashi K, Nakamura-Ishizu A, Kurokawa M, Iwama A, Okamoto S, Kataoka K, Takubo K. A culture platform to study quiescent hematopoietic stem cells following genome editing. CELL REPORTS METHODS 2022; 2:100354. [PMID: 36590688 PMCID: PMC9795334 DOI: 10.1016/j.crmeth.2022.100354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 04/06/2022] [Accepted: 11/03/2022] [Indexed: 12/12/2022]
Abstract
Other than genetically engineered mice, few reliable platforms are available for the study of hematopoietic stem cell (HSC) quiescence. Here we present a platform to analyze HSC cell cycle quiescence by combining culture conditions that maintain quiescence with a CRISPR-Cas9 genome editing system optimized for HSCs. We demonstrate that preculture of HSCs enhances editing efficiency by facilitating nuclear transport of ribonucleoprotein complexes. For post-editing culture, mouse and human HSCs edited based on non-homologous end joining and cultured under low-cytokine, low-oxygen, and high-albumin conditions retain their phenotypes and quiescence better than those cultured under the proliferative conditions. Using this approach, HSCs regain quiescence even after editing by homology-directed repair. Our results show that low-cytokine culture conditions for gene-edited HSCs are a useful approach for investigating HSC quiescence ex vivo.
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Affiliation(s)
- Kohei Shiroshita
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hiroshi Kobayashi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Shintaro Watanuki
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Daiki Karigane
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yuriko Sorimachi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Shinya Fujita
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Shinpei Tamaki
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Miho Haraguchi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
| | - Naoki Itokawa
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Kazumasa Aoyoama
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Shuhei Koide
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
| | - Yosuke Masamoto
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Kenta Kobayashi
- Section of Viral Vector Development, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Aichi 444-8585, Japan
| | - Ayako Nakamura-Ishizu
- Department of Microscopic and Developmental Anatomy, Tokyo Women’s Medical University, Tokyo 162-8666, Japan
| | - Mineo Kurokawa
- Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan
| | - Atsushi Iwama
- Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
- Laboratory of Cellular and Molecular Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan
| | - Shinichiro Okamoto
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Keisuke Kataoka
- Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan
| | - Keiyo Takubo
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan
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28
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Feyen J, Ping Z, Chen L, van Dijk C, van Tienhoven TVD, van Strien PMH, Hoogenboezem RM, Wevers MJW, Sanders MA, Touw IP, Raaijmakers MHGP. Myeloid cells promote interferon signaling-associated deterioration of the hematopoietic system. Nat Commun 2022; 13:7657. [PMID: 36496394 PMCID: PMC9741615 DOI: 10.1038/s41467-022-35318-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
Innate and adaptive immune cells participate in the homeostatic regulation of hematopoietic stem cells (HSCs). Here, we interrogate the contribution of myeloid cells, the most abundant cell type in the mammalian bone marrow, in a clinically relevant mouse model of neutropenia. Long-term genetic depletion of neutrophils and eosinophils results in activation of multipotent progenitors but preservation of HSCs. Depletion of myeloid cells abrogates HSC expansion, loss of serial repopulation and lymphoid reconstitution capacity and remodeling of HSC niches, features previously associated with hematopoietic aging. This is associated with mitigation of interferon signaling in both HSCs and their niches via reduction of NK cell number and activation. These data implicate myeloid cells in the functional decline of hematopoiesis, associated with activation of interferon signaling via a putative neutrophil-NK cell axis. Innate immunity may thus come at the cost of system deterioration through enhanced chronic inflammatory signaling to stem cells and their niches.
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Affiliation(s)
- Jacqueline Feyen
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
| | - Zhen Ping
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
| | - Lanpeng Chen
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
| | - Claire van Dijk
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
| | - Tim V. D. van Tienhoven
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
| | - Paulina M. H. van Strien
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
| | - Remco M. Hoogenboezem
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
| | - Michiel J. W. Wevers
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
| | - Mathijs A. Sanders
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
| | - Ivo P. Touw
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
| | - Marc H. G. P. Raaijmakers
- grid.508717.c0000 0004 0637 3764Department of Hematology, Erasmus MC Cancer Institute, 3015CN Rotterdam, the Netherlands
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29
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Rincon JC, Efron PA, Moldawer LL. Immunopathology of chronic critical illness in sepsis survivors: Role of abnormal myelopoiesis. J Leukoc Biol 2022; 112:1525-1534. [PMID: 36193662 PMCID: PMC9701155 DOI: 10.1002/jlb.4mr0922-690rr] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 09/09/2022] [Accepted: 09/14/2022] [Indexed: 02/01/2023] Open
Abstract
Sepsis remains the single most common cause of mortality and morbidity in hospitalized patients requiring intensive care. Although earlier detection and improved treatment bundles have reduced in-hospital mortality, long-term recovery remains dismal. Sepsis survivors who experience chronic critical illness often demonstrate persistent inflammation, immune suppression, lean tissue wasting, and physical and functional cognitive declines, which often last in excess of 1 year. Older patients and those with preexisting comorbidities may never fully recover and have increased mortality compared with individuals who restore their immunologic homeostasis. Many of these responses are shared with individuals with advanced cancer, active autoimmune diseases, chronic obstructive pulmonary disease, and chronic renal disease. Here, we propose that this resulting immunologic endotype is secondary to a persistent maladaptive reprioritization of myelopoiesis and pathologic activation of myeloid cells. Driven in part by the continuing release of endogenous alarmins from chronic organ injury and muscle wasting, as well as by secondary opportunistic infections, ongoing myelopoiesis at the expense of lymphopoiesis and erythropoiesis leads to anemia, recurring infections, and lean tissue wasting. Early recognition and intervention are required to interrupt this pathologic activation of myeloid populations.
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Affiliation(s)
- Jaimar C Rincon
- Sepsis and Critical Illness Research Center, Laboratory of Inflammation Biology and Surgical Science, Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Philip A Efron
- Sepsis and Critical Illness Research Center, Laboratory of Inflammation Biology and Surgical Science, Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Lyle L Moldawer
- Sepsis and Critical Illness Research Center, Laboratory of Inflammation Biology and Surgical Science, Department of Surgery, University of Florida College of Medicine, Gainesville, Florida, USA
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30
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Hasselbalch H, Skov V, Kjær L, Larsen MK, Knudsen TA, Lucijanić M, Kusec R. Recombinant Interferon-β in the Treatment of Polycythemia Vera and Related Neoplasms: Rationales and Perspectives. Cancers (Basel) 2022; 14:5495. [PMID: 36428587 PMCID: PMC9688061 DOI: 10.3390/cancers14225495] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/25/2022] [Accepted: 11/02/2022] [Indexed: 11/12/2022] Open
Abstract
About 30 years ago, the first clinical trials of the safety and efficacy of recombinant interferon-α2 (rIFN-α2) were performed. Since then, several single-arm studies have shown rIFN-α2 to be a highly potent anticancer agent against several cancer types. Unfortunately, however, a high toxicity profile in early studies with rIFN-α2 -among other reasons likely due to the high dosages being used-disqualified rIFN-α2, which was accordingly replaced with competitive drugs that might at first glance look more attractive to clinicians. Later, pegylated IFN-α2a (Pegasys) and pegylated IFN-α2b (PegIntron) were introduced, which have since been reported to be better tolerated due to reduced toxicity. Today, treatment with rIFN-α2 is virtually outdated in non-hematological cancers, where other immunotherapies-e.g., immune-checkpoint inhibitors-are routinely used in several cancer types and are being intensively investigated in others, either as monotherapy or in combination with immunomodulatory agents, although only rarely in combination with rIFN-α2. Within the hematological malignancies, rIFN-α2 has been used off-label for decades in patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPNs)-i.e., essential thrombocythemia, polycythemia vera, and myelofibrosis-and in recent years rIFN-α2 has been revived with the marketing of ropeginterferon-α2b (Besremi) for the treatment of polycythemia vera patients. Additionally, rIFN-α2 has been revived for the treatment of chronic myelogenous leukemia in combination with tyrosine kinase inhibitors. Another rIFN formulation-recombinant interferon-β (rIFN-β)-has been used for decades in the treatment of multiple sclerosis but has never been studied as a potential agent to be used in patients with MPNs, although several studies and reviews have repeatedly described rIFN-β as an effective anticancer agent as well. In this paper, we describe the rationales and perspectives for launching studies on the safety and efficacy of rIFN-β in patients with MPNs.
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Affiliation(s)
- Hans Hasselbalch
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | - Vibe Skov
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | - Lasse Kjær
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | | | - Trine A. Knudsen
- Department of Hematology, Zealand University, 4000 Roskilde, Denmark
| | - Marko Lucijanić
- Department of Hematology, University Hospital Dubrava, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Rajko Kusec
- Department of Hematology, University Hospital Dubrava, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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31
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Kobayashi H, Watanuki S, Takubo K. Approaches towards Elucidating the Metabolic Program of Hematopoietic Stem/Progenitor Cells. Cells 2022; 11:cells11203189. [PMID: 36291056 PMCID: PMC9600258 DOI: 10.3390/cells11203189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/27/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
Hematopoietic stem cells (HSCs) in bone marrow continuously supply a large number of blood cells throughout life in collaboration with hematopoietic progenitor cells (HPCs). HSCs and HPCs are thought to regulate and utilize intracellular metabolic programs to obtain metabolites, such as adenosine triphosphate (ATP), which is necessary for various cellular functions. Metabolites not only provide stem/progenitor cells with nutrients for ATP and building block generation but are also utilized for protein modification and epigenetic regulation to maintain cellular characteristics. In recent years, the metabolic programs of tissue stem/progenitor cells and their underlying molecular mechanisms have been elucidated using a variety of metabolic analysis methods. In this review, we first present the advantages and disadvantages of the current approaches applicable to the metabolic analysis of tissue stem/progenitor cells, including HSCs and HPCs. In the second half, we discuss the characteristics and regulatory mechanisms of HSC metabolism, including the decoupling of ATP production by glycolysis and mitochondria. These technologies and findings have the potential to advance stem cell biology and engineering from a metabolic perspective and to establish therapeutic approaches.
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32
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Singh S, Sarkar T, Jakubison B, Gadomski S, Spradlin A, Gudmundsson KO, Keller JR. Inhibitor of DNA binding proteins revealed as orchestrators of steady state, stress and malignant hematopoiesis. Front Immunol 2022; 13:934624. [PMID: 35990659 PMCID: PMC9389078 DOI: 10.3389/fimmu.2022.934624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/12/2022] [Indexed: 11/24/2022] Open
Abstract
Adult mammalian hematopoiesis is a dynamic cellular process that provides a continuous supply of myeloid, lymphoid, erythroid/megakaryocyte cells for host survival. This process is sustained by regulating hematopoietic stem cells (HSCs) quiescence, proliferation and activation under homeostasis and stress, and regulating the proliferation and differentiation of downstream multipotent progenitor (MPP) and more committed progenitor cells. Inhibitor of DNA binding (ID) proteins are small helix-loop-helix (HLH) proteins that lack a basic (b) DNA binding domain present in other family members, and function as dominant-negative regulators of other bHLH proteins (E proteins) by inhibiting their transcriptional activity. ID proteins are required for normal T cell, B cell, NK and innate lymphoid cells, dendritic cell, and myeloid cell differentiation and development. However, recent evidence suggests that ID proteins are important regulators of normal and leukemic hematopoietic stem and progenitor cells (HSPCs). This chapter will review our current understanding of the function of ID proteins in HSPC development and highlight future areas of scientific investigation.
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Affiliation(s)
- Shweta Singh
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI)- Frederick, Frederick, MD, United States
| | - Tanmoy Sarkar
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI)- Frederick, Frederick, MD, United States
| | - Brad Jakubison
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI)- Frederick, Frederick, MD, United States
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Stephen Gadomski
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI)- Frederick, Frederick, MD, United States
| | - Andrew Spradlin
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI)- Frederick, Frederick, MD, United States
| | - Kristbjorn O. Gudmundsson
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI)- Frederick, Frederick, MD, United States
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
| | - Jonathan R. Keller
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI)- Frederick, Frederick, MD, United States
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States
- *Correspondence: Jonathan R. Keller,
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33
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Dozzo A, Galvin A, Shin JW, Scalia S, O'Driscoll CM, Ryan KB. Modelling acute myeloid leukemia (AML): What's new? A transition from the classical to the modern. Drug Deliv Transl Res 2022:10.1007/s13346-022-01189-4. [PMID: 35930221 DOI: 10.1007/s13346-022-01189-4] [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] [Accepted: 05/24/2022] [Indexed: 11/24/2022]
Abstract
Acute myeloid leukemia (AML) is a heterogeneous malignancy affecting myeloid cells in the bone marrow (BM) but can spread giving rise to impaired hematopoiesis. AML incidence increases with age and is associated with poor prognostic outcomes. There has been a disconnect between the success of novel drug compounds observed in preclinical studies of hematological malignancy and less than exceptional therapeutic responses in clinical trials. This review aims to provide a state-of-the-art overview on the different preclinical models of AML available to expand insights into disease pathology and as preclinical screening tools. Deciphering the complex physiological and pathological processes and developing predictive preclinical models are key to understanding disease progression and fundamental in the development and testing of new effective drug treatments. Standard scaffold-free suspension models fail to recapitulate the complex environment where AML occurs. To this end, we review advances in scaffold/matrix-based 3D models and outline the most recent advances in on-chip technology. We also provide an overview of clinically relevant animal models and review the expanding use of patient-derived samples, which offer the prospect to create more "patient specific" screening tools either in the guise of 3D matrix models, microphysiological "organ-on-chip" tools or xenograft models and discuss representative examples.
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Affiliation(s)
| | - Aoife Galvin
- School of Pharmacy, University College Cork, Cork, Ireland
| | - Jae-Won Shin
- Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago College of Medicine, 909 S. Wolcott Ave, Chicago, IL, 5091 COMRB, USA
| | - Santo Scalia
- Università degli Studi di Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy
| | - Caitriona M O'Driscoll
- School of Pharmacy, University College Cork, Cork, Ireland.,SSPC Centre for Pharmaceutical Research, School of Pharmacy, University College Cork, Cork, Ireland
| | - Katie B Ryan
- School of Pharmacy, University College Cork, Cork, Ireland. .,SSPC Centre for Pharmaceutical Research, School of Pharmacy, University College Cork, Cork, Ireland.
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34
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Epigenetic Memories in Hematopoietic Stem and Progenitor Cells. Cells 2022; 11:cells11142187. [PMID: 35883630 PMCID: PMC9324604 DOI: 10.3390/cells11142187] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/06/2022] [Accepted: 07/11/2022] [Indexed: 11/16/2022] Open
Abstract
The recent development of next-generation sequencing (NGS) technologies has contributed to research into various biological processes. These novel NGS technologies have revealed the involvement of epigenetic memories in trained immunity, which are responses to transient stimulation and result in better responses to secondary challenges. Not only innate system cells, such as macrophages, monocytes, and natural killer cells, but also bone marrow hematopoietic stem cells (HSCs) have been found to gain memories upon transient stimulation, leading to the enhancement of responses to secondary challenges. Various stimuli, including microbial infection, can induce the epigenetic reprogramming of innate immune cells and HSCs, which can result in an augmented response to secondary stimulation. In this review, we introduce novel NGS technologies and their application to unraveling epigenetic memories that are key in trained immunity and summarize the recent findings in trained immunity. We also discuss our most recent finding regarding epigenetic memory in aged HSCs, which may be associated with the exposure of HSCs to aging-related stresses.
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35
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Zhang YW, Mess J, Aizarani N, Mishra P, Johnson C, Romero-Mulero MC, Rettkowski J, Schönberger K, Obier N, Jäcklein K, Woessner NM, Lalioti ME, Velasco-Hernandez T, Sikora K, Wäsch R, Lehnertz B, Sauvageau G, Manke T, Menendez P, Walter SG, Minguet S, Laurenti E, Günther S, Grün D, Cabezas-Wallscheid N. Hyaluronic acid-GPRC5C signalling promotes dormancy in haematopoietic stem cells. Nat Cell Biol 2022; 24:1038-1048. [PMID: 35725769 PMCID: PMC9276531 DOI: 10.1038/s41556-022-00931-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 05/02/2022] [Indexed: 12/11/2022]
Abstract
Bone marrow haematopoietic stem cells (HSCs) are vital for lifelong maintenance of healthy haematopoiesis. In inbred mice housed in gnotobiotic facilities, the top of the haematopoietic hierarchy is occupied by dormant HSCs, which reversibly exit quiescence during stress. Whether HSC dormancy exists in humans remains debatable. Here, using single-cell RNA sequencing, we show a continuous landscape of highly purified human bone marrow HSCs displaying varying degrees of dormancy. We identify the orphan receptor GPRC5C, which enriches for dormant human HSCs. GPRC5C is also essential for HSC function, as demonstrated by genetic loss- and gain-of-function analyses. Through structural modelling and biochemical assays, we show that hyaluronic acid, a bone marrow extracellular matrix component, preserves dormancy through GPRC5C. We identify the hyaluronic acid-GPRC5C signalling axis controlling the state of dormancy in mouse and human HSCs.
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Affiliation(s)
- Yu Wei Zhang
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany.,International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany
| | - Julian Mess
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany.,Spemann Graduate School for Biology and Medicine (SGBM), Freiburg, Germany.,Centre for Integrative Biological Signalling Studies (CIBSS), Freiburg, Germany
| | - Nadim Aizarani
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany.,International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany
| | - Pankaj Mishra
- Pharmaceutical Bioinformatics, University of Freiburg, Freiburg, Germany
| | - Carys Johnson
- Department of Haematology and Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Mari Carmen Romero-Mulero
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Jasmin Rettkowski
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany.,Spemann Graduate School for Biology and Medicine (SGBM), Freiburg, Germany
| | - Katharina Schönberger
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany.,International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Freiburg, Germany
| | - Nadine Obier
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Karin Jäcklein
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Nadine M Woessner
- Faculty of Biology, University of Freiburg, Freiburg, Germany.,Spemann Graduate School for Biology and Medicine (SGBM), Freiburg, Germany.,Centre for Integrative Biological Signalling Studies (CIBSS), Freiburg, Germany.,Signalling Research Center BIOSS, Freiburg, Germany
| | | | - Talia Velasco-Hernandez
- Josep Carreras Leukemia Research Institute-Campus Clinic and Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain
| | - Katarzyna Sikora
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Ralph Wäsch
- Department of Hematology, Oncology and Stem Cell Transplantation, Faculty of Medical, University of Freiburg, Freiburg, Germany
| | - Bernhard Lehnertz
- Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
| | - Guy Sauvageau
- Institute for Research in Immunology and Cancer, University of Montreal, Montreal, Canada
| | - Thomas Manke
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Pablo Menendez
- Signalling Research Center BIOSS, Freiburg, Germany.,Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.,Spanish Network for Cancer Research (CIBER-ONC)-ISCIII, Barcelona, Spain
| | | | - Susana Minguet
- Faculty of Biology, University of Freiburg, Freiburg, Germany.,Centre for Integrative Biological Signalling Studies (CIBSS), Freiburg, Germany.,Signalling Research Center BIOSS, Freiburg, Germany
| | - Elisa Laurenti
- Department of Haematology and Wellcome and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Stefan Günther
- Pharmaceutical Bioinformatics, University of Freiburg, Freiburg, Germany
| | - Dominic Grün
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.,Centre for Integrative Biological Signalling Studies (CIBSS), Freiburg, Germany.,Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität, Würzburg, Germany.,Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI), Würzburg, Germany
| | - Nina Cabezas-Wallscheid
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. .,Centre for Integrative Biological Signalling Studies (CIBSS), Freiburg, Germany.
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36
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Jakubison BL, Sarkar T, Gudmundsson KO, Singh S, Sun L, Morris HM, Klarmann KD, Keller JR. ID2 and HIF-1α collaborate to protect quiescent hematopoietic stem cells from activation, differentiation, and exhaustion. J Clin Invest 2022; 132:152599. [PMID: 35775482 PMCID: PMC9246389 DOI: 10.1172/jci152599] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 04/26/2022] [Indexed: 11/17/2022] Open
Abstract
Defining mechanism(s) that maintain tissue stem quiescence is important for improving tissue regeneration, cell therapies, aging, and cancer. We report here that genetic ablation of Id2 in adult hematopoietic stem cells (HSCs) promotes increased HSC activation and differentiation, which results in HSC exhaustion and bone marrow failure over time. Id2Δ/Δ HSCs showed increased cycling, ROS production, mitochondrial activation, ATP production, and DNA damage compared with Id2+/+ HSCs, supporting the conclusion that Id2Δ/Δ HSCs are less quiescent. Mechanistically, HIF-1α expression was decreased in Id2Δ/Δ HSCs, and stabilization of HIF-1α in Id2Δ/Δ HSCs restored HSC quiescence and rescued HSC exhaustion. Inhibitor of DNA binding 2 (ID2) promoted HIF-1α expression by binding to the von Hippel-Lindau (VHL) protein and interfering with proteasomal degradation of HIF-1α. HIF-1α promoted Id2 expression and enforced a positive feedback loop between ID2 and HIF-1α to maintain HSC quiescence. Thus, sustained ID2 expression could protect HSCs during stress and improve HSC expansion for gene editing and cell therapies.
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Affiliation(s)
- Brad L Jakubison
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.,Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI) - Frederick, NIH, Frederick, Maryland, USA
| | - Tanmoy Sarkar
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI) - Frederick, NIH, Frederick, Maryland, USA
| | - Kristbjorn O Gudmundsson
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.,Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI) - Frederick, NIH, Frederick, Maryland, USA
| | - Shweta Singh
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI) - Frederick, NIH, Frederick, Maryland, USA
| | - Lei Sun
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI) - Frederick, NIH, Frederick, Maryland, USA
| | - Holly M Morris
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI) - Frederick, NIH, Frederick, Maryland, USA
| | - Kimberly D Klarmann
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA
| | - Jonathan R Keller
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.,Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute (NCI) - Frederick, NIH, Frederick, Maryland, USA
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37
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Romiplostim addition to conditioning prior to HSCT allows chemotherapy reduction while maintaining engraftment levels. Blood Adv 2022; 6:4485-4489. [PMID: 35736667 DOI: 10.1182/bloodadvances.2022007566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 06/20/2022] [Indexed: 11/20/2022] Open
Abstract
Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) offers are curative treatment approach for certain benign and malignant hematologic diseases. The actual HSCT is preceded by a conditioning therapy that reduces host-versus HSCT graft rejection and creates niche space for transplanted Hematopoietic Stem and Progenitor Cells (HSPCs). Conditioning consists of chemotherapy with or without irradiation and is a major cause of side-effects in HSCT. However, reduction of the intensity of cytotoxic conditioning leads to higher rates of engrafment failure and increased rates of relapse. In the present study, we investigated in how far sensitization of HSPCs to chemotherapy allows a reduction of the dose of drugs used as conditioning regimen in an HSCT mouse model. The thrombopoietin receptor agonist Romiplostim was shown to induce cell cycling activity in Hematopoietic Stem Cells (HSCs). We thus tested if the addition of Romiplostim to the clinically applied conditioning chemotherapy regimen cyclophosphamide and busulfan leads to increased efficacy of the chemotherapeutic regimen. We found that Romiplostim not only sensitizes HSCs to chemotherapy but also enables a reduction of the main chemotherapeutic component Busulfan by half, while HSC engraftment levels are maintained in long-term, serial transplantation assays.
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38
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Expansion of Quiescent Hematopoietic Stem Cells under Stress and Nonstress Conditions in Mice. Stem Cell Rev Rep 2022; 18:2388-2402. [DOI: 10.1007/s12015-022-10380-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/15/2022] [Indexed: 11/25/2022]
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39
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A complex proinflammatory cascade mediates the activation of HSCs upon LPS exposure in vivo. Blood Adv 2022; 6:3513-3528. [PMID: 35413096 PMCID: PMC9198917 DOI: 10.1182/bloodadvances.2021006088] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 03/13/2022] [Indexed: 11/22/2022] Open
Abstract
HSCs are transiently activated by acute LPS challenge via direct and indirect mechanisms, including CD115+ monocytic cells in BM. The combined action of IFNα, IFNγ, TNFα, IL-1α, IL-1β, and other cytokines is required to mediate HSC activation in response to LPS in vivo. Infections are a key source of stress to the hematopoietic system. While infections consume short-lived innate immune cells, their recovery depends on quiescent hematopoietic stem cells (HSCs) with long-term self-renewal capacity. Both chronic inflammatory stress and bacterial infections compromise competitive HSC capacity and cause bone marrow (BM) failure. However, our understanding of how HSCs act during acute and contained infections remains incomplete. Here, we used advanced chimeric and genetic mouse models in combination with pharmacological interventions to dissect the complex nature of the acute systemic response of HSCs to lipopolysaccharide (LPS), a well-established model for inducing inflammatory stress. Acute LPS challenge transiently induced proliferation of quiescent HSCs in vivo. This response was not only mediated via direct LPS-TLR4 conjugation on HSCs but also involved indirect TLR4 signaling in CD115+ monocytic cells, inducing a complex proinflammatory cytokine cascade in BM. Downstream of LPS-TLR4 signaling, the combined action of proinflammatory cytokines such as interferon (IFN)α, IFNγ, tumor necrosis factor-α, interleukin (IL)-1α, IL-1β, and many others is required to mediate full HSC activation in vivo. Together, our study reveals detailed mechanistic insights into the interplay of proinflammatory cytokine-induced molecular pathways and cell types that jointly orchestrate the complex process of emergency hematopoiesis and HSC activation upon LPS exposure in vivo.
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40
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Mayer IM, Hoelbl-Kovacic A, Sexl V, Doma E. Isolation, Maintenance and Expansion of Adult Hematopoietic Stem/Progenitor Cells and Leukemic Stem Cells. Cancers (Basel) 2022; 14:1723. [PMID: 35406494 PMCID: PMC8996967 DOI: 10.3390/cancers14071723] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/23/2022] [Accepted: 03/25/2022] [Indexed: 12/12/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are rare, self-renewing cells that perch on top of the hematopoietic tree. The HSCs ensure the constant supply of mature blood cells in a tightly regulated process producing peripheral blood cells. Intense efforts are ongoing to optimize HSC engraftment as therapeutic strategy to treat patients suffering from hematopoietic diseases. Preclinical research paves the way by developing methods to maintain, manipulate and expand HSCs ex vivo to understand their regulation and molecular make-up. The generation of a sufficient number of transplantable HSCs is the Holy Grail for clinical therapy. Leukemia stem cells (LSCs) are characterized by their acquired stem cell characteristics and are responsible for disease initiation, progression, and relapse. We summarize efforts, that have been undertaken to increase the number of long-term (LT)-HSCs and to prevent differentiation towards committed progenitors in ex vivo culture. We provide an overview and compare methods currently available to isolate, maintain and enrich HSC subsets, progenitors and LSCs and discuss their individual advantages and drawbacks.
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Affiliation(s)
| | | | - Veronika Sexl
- Institute of Pharmacology and Toxicology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria; (I.M.M.); (A.H.-K.); (E.D.)
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41
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Mann Z, Sengar M, Verma YK, Rajalingam R, Raghav PK. Hematopoietic Stem Cell Factors: Their Functional Role in Self-Renewal and Clinical Aspects. Front Cell Dev Biol 2022; 10:664261. [PMID: 35399522 PMCID: PMC8987924 DOI: 10.3389/fcell.2022.664261] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 02/14/2022] [Indexed: 01/29/2023] Open
Abstract
Hematopoietic stem cells (HSCs) possess two important properties such as self-renewal and differentiation. These properties of HSCs are maintained through hematopoiesis. This process gives rise to two subpopulations, long-term and short-term HSCs, which have become a popular convention for treating various hematological disorders. The clinical application of HSCs is bone marrow transplant in patients with aplastic anemia, congenital neutropenia, sickle cell anemia, thalassemia, or replacement of damaged bone marrow in case of chemotherapy. The self-renewal attribute of HSCs ensures long-term hematopoiesis post-transplantation. However, HSCs need to be infused in large numbers to reach their target site and meet the demands since they lose their self-renewal capacity after a few passages. Therefore, a more in-depth understanding of ex vivo HSCs expansion needs to be developed to delineate ways to enhance the self-renewability of isolated HSCs. The multifaceted self-renewal process is regulated by factors, including transcription factors, miRNAs, and the bone marrow niche. A developed classical hierarchical model that outlines the hematopoiesis in a lineage-specific manner through in vivo fate mapping, barcoding, and determination of self-renewal regulatory factors are still to be explored in more detail. Thus, an in-depth study of the self-renewal property of HSCs is essentially required to be utilized for ex vivo expansion. This review primarily focuses on the Hematopoietic stem cell self-renewal pathway and evaluates the regulatory molecular factors involved in considering a targeted clinical approach in numerous malignancies and outlining gaps in the current knowledge.
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Affiliation(s)
- Zoya Mann
- Independent Researcher, New Delhi, India
| | - Manisha Sengar
- Department of Zoology, Deshbandhu College, University of Delhi, Delhi, India
| | - Yogesh Kumar Verma
- Stem Cell and Gene Therapy Research Group, Institute of Nuclear Medicine and Allied Sciences (INMAS), Delhi, India
| | - Raja Rajalingam
- Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Pawan Kumar Raghav
- Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, CA, United States
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42
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Umemoto T, Johansson A, Ahmad SAI, Hashimoto M, Kubota S, Kikuchi K, Odaka H, Era T, Kurotaki D, Sashida G, Suda T. ATP citrate lyase controls hematopoietic stem cell fate and supports bone marrow regeneration. EMBO J 2022; 41:e109463. [PMID: 35229328 PMCID: PMC9016348 DOI: 10.15252/embj.2021109463] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 01/21/2022] [Accepted: 01/25/2022] [Indexed: 01/08/2023] Open
Abstract
In order to support bone marrow regeneration after myeloablation, hematopoietic stem cells (HSCs) actively divide to provide both stem and progenitor cells. However, the mechanisms regulating HSC function and cell fate choice during hematopoietic recovery remain unclear. We herein provide novel insights into HSC regulation during regeneration by focusing on mitochondrial metabolism and ATP citrate lyase (ACLY). After 5-fluorouracil-induced myeloablation, HSCs highly expressing endothelial protein C receptor (EPCRhigh ) were enriched within the stem cell fraction at the expense of more proliferative EPCRLow HSCs. These EPCRHigh HSCs were initially more primitive than EPCRLow HSCs and enabled stem cell expansion by enhancing histone acetylation, due to increased activity of ACLY in the early phase of hematopoietic regeneration. In the late phase of recovery, HSCs enhanced differentiation potential by increasing the accessibility of cis-regulatory elements in progenitor cell-related genes, such as CD48. In conditions of reduced mitochondrial metabolism and ACLY activity, these HSCs maintained stem cell phenotypes, while ACLY-dependent histone acetylation promoted differentiation into CD48+ progenitor cells. Collectively, these results indicate that the dynamic control of ACLY-dependent metabolism and epigenetic alterations is essential for HSC regulation during hematopoietic regeneration.
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Affiliation(s)
- Terumasa Umemoto
- Laboratory of Hematopoietic Stem Cell EngineeringInternational Research Center for Medical SciencesKumamoto UniversityKumamotoJapan
| | - Alban Johansson
- Laboratory of Hematopoietic Stem Cell EngineeringInternational Research Center for Medical SciencesKumamoto UniversityKumamotoJapan
| | - Shah Adil Ishtiyaq Ahmad
- Laboratory of Hematopoietic Stem Cell EngineeringInternational Research Center for Medical SciencesKumamoto UniversityKumamotoJapan
| | - Michihiro Hashimoto
- Laboratory of Stem Cell RegulationInternational Research Center for Medical SciencesKumamoto UniversityKumamotoJapan
| | - Sho Kubota
- Laboratory of Transcriptional Regulation in LeukemogenesisInternational Research Center for Medical SciencesKumamoto UniversityKumamotoJapan
| | - Kenta Kikuchi
- Laboratory of Chromatin Organization in Immune Cell DevelopmentInternational Research Center for Medical SciencesKumamoto UniversityKumamotoJapan
| | - Haruki Odaka
- Department of Cell ModulationInstitute of Molecular Embryology and GeneticsKumamoto UniversityKumamotoJapan
| | - Takumi Era
- Department of Cell ModulationInstitute of Molecular Embryology and GeneticsKumamoto UniversityKumamotoJapan
| | - Daisuke Kurotaki
- Laboratory of Chromatin Organization in Immune Cell DevelopmentInternational Research Center for Medical SciencesKumamoto UniversityKumamotoJapan
| | - Goro Sashida
- Laboratory of Transcriptional Regulation in LeukemogenesisInternational Research Center for Medical SciencesKumamoto UniversityKumamotoJapan
| | - Toshio Suda
- Laboratory of Stem Cell RegulationInternational Research Center for Medical SciencesKumamoto UniversityKumamotoJapan,Cancer Science Institute of SingaporeNational University of SingaporeSingapore CitySingapore
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43
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Hematopoietic Progenitors and the Bone Marrow Niche Shape the Inflammatory Response and Contribute to Chronic Disease. Int J Mol Sci 2022; 23:ijms23042234. [PMID: 35216355 PMCID: PMC8879433 DOI: 10.3390/ijms23042234] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 11/17/2022] Open
Abstract
It is now well understood that the bone marrow (BM) compartment can sense systemic inflammatory signals and adapt through increased proliferation and lineage skewing. These coordinated and dynamic alterations in responding hematopoietic stem and progenitor cells (HSPCs), as well as in cells of the bone marrow niche, are increasingly viewed as key contributors to the inflammatory response. Growth factors, cytokines, metabolites, microbial products, and other signals can cause dysregulation across the entire hematopoietic hierarchy, leading to lineage-skewing and even long-term functional adaptations in bone marrow progenitor cells. These alterations may play a central role in the chronicity of disease as well as the links between many common chronic disorders. The possible existence of a form of “memory” in bone marrow progenitor cells is thought to contribute to innate immune responses via the generation of trained immunity (also called innate immune memory). These findings highlight how hematopoietic progenitors dynamically adapt to meet the demand for innate immune cells and how this adaptive response may be beneficial or detrimental depending on the context. In this review, we will discuss the role of bone marrow progenitor cells and their microenvironment in shaping the scope and scale of the immune response in health and disease.
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44
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Yang Y, Kueh AJ, Grant ZL, Abeysekera W, Garnham AL, Wilcox S, Hyland CD, Di Rago L, Metcalf D, Alexander WS, Coultas L, Smyth GK, Voss AK, Thomas T. The histone lysine acetyltransferase HBO1 (KAT7) regulates hematopoietic stem cell quiescence and self-renewal. Blood 2022; 139:845-858. [PMID: 34724565 DOI: 10.1182/blood.2021013954] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/13/2021] [Indexed: 11/20/2022] Open
Abstract
The histone acetyltransferase HBO1 (MYST2, KAT7) is indispensable for postgastrulation development, histone H3 lysine 14 acetylation (H3K14Ac), and the expression of embryonic patterning genes. In this study, we report the role of HBO1 in regulating hematopoietic stem cell function in adult hematopoiesis. We used 2 complementary cre-recombinase transgenes to conditionally delete Hbo1 (Mx1-Cre and Rosa26-CreERT2). Hbo1-null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow 2 to 6 weeks after Hbo1 deletion. Hbo1-deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Hbo1 deletion caused a rapid loss of hematopoietic progenitors. The numbers of lineage-restricted progenitors for the erythroid, myeloid, B-, and T-cell lineages were reduced. Loss of HBO1 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, genes important for HSC functions were downregulated in HSC-enriched cell populations after Hbo1 deletion, including genes essential for HSC quiescence and self-renewal, such as Mpl, Tek(Tie-2), Gfi1b, Egr1, Tal1(Scl), Gata2, Erg, Pbx1, Meis1, and Hox9, as well as genes important for multipotent progenitor cells and lineage-specific progenitor cells, such as Gata1. HBO1 was required for H3K14Ac through the genome and particularly at gene loci required for HSC quiescence and self-renewal. Our data indicate that HBO1 promotes the expression of a transcription factor network essential for HSC maintenance and self-renewal in adult hematopoiesis.
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Affiliation(s)
- Yuqing Yang
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- Department of Medical Biology and
| | - Andrew J Kueh
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- Department of Medical Biology and
| | - Zoe L Grant
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- Department of Medical Biology and
| | - Waruni Abeysekera
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- Department of Medical Biology and
| | - Alexandra L Garnham
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- Department of Medical Biology and
| | - Stephen Wilcox
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
| | - Craig D Hyland
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
| | - Ladina Di Rago
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
| | - Don Metcalf
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- Department of Medical Biology and
| | - Warren S Alexander
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- Department of Medical Biology and
| | - Leigh Coultas
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- Department of Medical Biology and
| | - Gordon K Smyth
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC, Australia
| | - Anne K Voss
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- Department of Medical Biology and
| | - Tim Thomas
- Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; and
- Department of Medical Biology and
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45
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Thankam FG, Huynh J, Fang W, Chen Y, Agrawal DK. Exosomal-ribosomal proteins-driven heterogeneity of epicardial adipose tissue derived stem cells under ischemia for cardiac regeneration. J Tissue Eng Regen Med 2022; 16:396-408. [PMID: 35142442 DOI: 10.1002/term.3289] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 01/19/2022] [Accepted: 01/31/2022] [Indexed: 12/22/2022]
Abstract
Extracellular ribosomal proteins secreted in exosomes elicit biological/regenerative responses; however, ribosomal proteins contained in the exosomes of ischemia-challenged epicardial adipose tissue-derived stem cells (EATDS) remain unexplored. This study focuses on the identification of ribosomal proteins in the exosomes of ischemia-challenged EATDS and their sub-populations based on the key ribosomal proteins using single-cell genomics. Exosomes were isolated from control, ischemic (ISC), and reperfused (ISC/R) EATDS harvested from hyperlipidemic microswine, and the proteins were detected using Liquid chromatography with tandem mass spectrometry (LC-MS/MS). One hundred ninety-nine proteins and 177 proteins were detected in ISC and ISC/R groups, respectively with significant fold-change compared to controls. Five ribosomal proteins, RPL10A, 40SRPS18, 40SRPS30, 60SRPL14, and 40SRPSA, were significant owing to their abundance based on LC-MS/MS data. Expression of these proteins, except RPL10A, at transcript and protein levels were lower in ISC group compared to the control. scRNAseq analysis revealed EATDS heterogeneity based on the upregulation of 40SRPSA, 40SRPL18, and 40SRPS18. Pro-inflammatory sub-populations upregulated CCL5, anti-inflammatory sub-population upregulated IL-11, proliferative sub-population upregulated cell cycle and DNA replication mediators, and non-proliferative population downregulated the cell cycle and DNA replication mediators. Overall, the functional role of extracellular ribosomal proteins in driving unique phenotypes of EATDS population offers promise for designing effective translational approaches for myocardial regeneration.
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Affiliation(s)
- Finosh G Thankam
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
| | - James Huynh
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
| | - William Fang
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
| | - Yu Chen
- Molecular Instrumentation Center, University of California-Los Angeles, Los Angeles, California, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, Pomona, California, USA
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46
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Fielding C, García-García A, Korn C, Gadomski S, Fang Z, Reguera JL, Pérez-Simón JA, Göttgens B, Méndez-Ferrer S. Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis. Nat Commun 2022; 13:543. [PMID: 35087060 PMCID: PMC8795384 DOI: 10.1038/s41467-022-28175-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 01/12/2022] [Indexed: 12/15/2022] Open
Abstract
The sympathetic nervous system has been evolutionary selected to respond to stress and activates haematopoietic stem cells via noradrenergic signals. However, the pathways preserving haematopoietic stem cell quiescence and maintenance under proliferative stress remain largely unknown. Here we found that cholinergic signals preserve haematopoietic stem cell quiescence in bone-associated (endosteal) bone marrow niches. Bone marrow cholinergic neural signals increase during stress haematopoiesis and are amplified through cholinergic osteoprogenitors. Lack of cholinergic innervation impairs balanced responses to chemotherapy or irradiation and reduces haematopoietic stem cell quiescence and self-renewal. Cholinergic signals activate α7 nicotinic receptor in bone marrow mesenchymal stromal cells leading to increased CXCL12 expression and haematopoietic stem cell quiescence. Consequently, nicotine exposure increases endosteal haematopoietic stem cell quiescence in vivo and impairs hematopoietic regeneration after haematopoietic stem cell transplantation in mice. In humans, smoking history is associated with delayed normalisation of platelet counts after allogeneic haematopoietic stem cell transplantation. These results suggest that cholinergic signals preserve stem cell quiescence under proliferative stress.
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Affiliation(s)
- Claire Fielding
- Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, CB2 0AW, UK
- Department of Hematology, University of Cambridge, Cambridge, CB2 0AW, UK
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK
| | - Andrés García-García
- Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, CB2 0AW, UK
- Department of Hematology, University of Cambridge, Cambridge, CB2 0AW, UK
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK
| | - Claudia Korn
- Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, CB2 0AW, UK
- Department of Hematology, University of Cambridge, Cambridge, CB2 0AW, UK
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK
| | - Stephen Gadomski
- Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, CB2 0AW, UK
- Department of Hematology, University of Cambridge, Cambridge, CB2 0AW, UK
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK
- Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, 20892, USA
- NIH-Oxford-Cambridge Scholars Program in partnership with Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Zijian Fang
- Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, CB2 0AW, UK
- Department of Hematology, University of Cambridge, Cambridge, CB2 0AW, UK
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK
| | - Juan L Reguera
- Department of Hematology, University Hospital Virgen del Rocio, 41013, Sevilla, Spain
| | - José A Pérez-Simón
- NIH-Oxford-Cambridge Scholars Program in partnership with Medical University of South Carolina, Charleston, SC, 29425, USA
- Department of Hematology, University Hospital Virgen del Rocio, 41013, Sevilla, Spain
| | - Berthold Göttgens
- Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, CB2 0AW, UK
- Department of Hematology, University of Cambridge, Cambridge, CB2 0AW, UK
| | - Simón Méndez-Ferrer
- Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, CB2 0AW, UK.
- Department of Hematology, University of Cambridge, Cambridge, CB2 0AW, UK.
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK.
- Instituto de Biomedicina de Sevilla (IBiS/CSIC), Universidad de Sevilla, 41013, Seville, Spain.
- Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, 41009, Seville, Spain.
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47
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Hsieh HL, Yu MC, Cheng LC, Yeh TS, Tsai MM. Molecular mechanism of therapeutic approaches for human gastric cancer stem cells. World J Stem Cells 2022; 14:76-91. [PMID: 35126829 PMCID: PMC8788185 DOI: 10.4252/wjsc.v14.i1.76] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/15/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a primary cause of cancer-related mortality worldwide, and even after therapeutic gastrectomy, survival rates remain poor. The presence of gastric cancer stem cells (GCSCs) is thought to be the major reason for resistance to anticancer treatment (chemotherapy or radiotherapy), and for the development of tumor recurrence, epithelial-mesenchymal transition, and metastases. Additionally, GCSCs have the capacity for self-renewal, differentiation, and tumor initiation. They also synthesize antiapoptotic factors, demonstrate higher performance of drug efflux pumps, and display cell plasticity abilities. Moreover, the tumor microenvironment (TME; tumor niche) that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor. However, the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential. In this review, we provide up-to-date information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development. This information will support improved diagnosis, novel therapeutic approaches, and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy. To date, most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents. However, when used in combination with adjuvant therapy, treatment can improve. By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC, the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy, radiotherapy, or other adjuvant treatment.
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Affiliation(s)
- Hsi-Lung Hsieh
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of Neurology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Ming-Chin Yu
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of General Surgery, New Taipei Municipal TuCheng Hospital, New Taipei 236, Taiwan
| | - Li-Ching Cheng
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
| | - Ta-Sen Yeh
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Ming-Ming Tsai
- Department of Nursing, Division of Basic Medical Sciences, Chang-Gung University of Science and Technology, Taoyuan 333, Taiwan
- Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
- Department of General Surgery, Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
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48
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Martinez P, Ballarin L, Ereskovsky AV, Gazave E, Hobmayer B, Manni L, Rottinger E, Sprecher SG, Tiozzo S, Varela-Coelho A, Rinkevich B. Articulating the "stem cell niche" paradigm through the lens of non-model aquatic invertebrates. BMC Biol 2022; 20:23. [PMID: 35057814 PMCID: PMC8781081 DOI: 10.1186/s12915-022-01230-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 01/12/2022] [Indexed: 12/13/2022] Open
Abstract
Stem cells (SCs) in vertebrates typically reside in "stem cell niches" (SCNs), morphologically restricted tissue microenvironments that are important for SC survival and proliferation. SCNs are broadly defined by properties including physical location, but in contrast to vertebrates and other "model" organisms, aquatic invertebrate SCs do not have clearly documented niche outlines or properties. Life strategies such as regeneration or asexual reproduction may have conditioned the niche architectural variability in aquatic or marine animal groups. By both establishing the invertebrates SCNs as independent types, yet allowing inclusiveness among them, the comparative analysis will allow the future functional characterization of SCNs.
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Affiliation(s)
- P Martinez
- Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona, Av. Diagonal 643, 08028, Barcelona, Spain.
- Institut Català de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
| | - L Ballarin
- Department of Biology, University of Padova, Via U. Bassi 58/B, 35100, Padova, Italy
| | - A V Ereskovsky
- Aix Marseille University, Avignon Université, CNRS, IRD, IMBE, Marseille, France
- St. Petersburg State University, Biological Faculty, Universitetskaya emb. 7/9, St. Petersburg, 199034, Russia
- N. K. Koltzov Institute of Developmental Biology, Russian Academy of Sciences, Vavilova Street 26, Moscow, 119334, Russia
| | - E Gazave
- Université de Paris, CNRS, Institut Jacques Monod, F-75006, Paris, France
| | - B Hobmayer
- Department of Zoology and Center of Molecular Biosciences, University of Innsbruck, Technikerstr. 25, 6020, Innsbruck, Austria
| | - L Manni
- Department of Biology, University of Padova, Via U. Bassi 58/B, 35100, Padova, Italy
| | - E Rottinger
- Université Côte d'Azur, CNRS, INSERM, Institute for Research on Cancer and Aging, Nice (IRCAN), Nice, France
- Université Côte d'Azur, Federative Research Institute - Marine Resources (IFR MARRES), Nice, France
| | - S G Sprecher
- Department of Biology, University of Fribourg, Chemin du Musee 10, 1700, Fribourg, Switzerland
| | - S Tiozzo
- Sorbonne Université, CNRS, Laboratoire de Biologie du Développement de Villefranche-sur-mer (LBDV), Paris, France
| | - A Varela-Coelho
- ITQB NOVA, Instituto de Tecnologia Química e Biológica António Xavier, Av. da República, 2780-157, Oeiras, Portugal
| | - B Rinkevich
- Israel Oceanography and Limnological Research, National Institute of Oceanography, Tel Shikmona, P.O. Box 8030, 31080, Haifa, Israel.
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49
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Evolution and Targeting of Myeloid Suppressor Cells in Cancer: A Translational Perspective. Cancers (Basel) 2022; 14:cancers14030510. [PMID: 35158779 PMCID: PMC8833347 DOI: 10.3390/cancers14030510] [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: 12/30/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Immunotherapy is achieving impressive results in the treatment of several cancers. While the main strategies aim to re-invigorate the specific lymphocyte anti-tumor response, many studies underline that altered myeloid cell frequency and functions can dramatically interfere with the responsiveness to cancer therapies. Therefore, many novel strategies targeting TAMs and MDSCs in combination with classical treatments are under continuous evolution at both pre-clinical and clinical levels, showing encouraging results. Herein, we depict a comprehensive overview of myeloid cell generation and function in a cancer setting, and the most relevant strategies for their targeting that are currently in clinical use or under pre-clinical development. Abstract In recent years, the immune system has emerged as a critical regulator of tumor development, progression and dissemination. Advanced therapeutic approaches targeting immune cells are currently under clinical use and improvement for the treatment of patients affected by advanced malignancies. Among these, anti-PD1/PD-L1 and anti-CTLA4 immune checkpoint inhibitors (ICIs) are the most effective immunotherapeutic drugs at present. In spite of these advances, great variability in responses to therapy exists among patients, probably due to the heterogeneity of both cancer cells and immune responses, which manifest in diverse forms in the tumor microenvironment (TME). The variability of the immune profile within TME and its prognostic significance largely depend on the frequency of the infiltrating myeloid cells, which often represent the predominant population, characterized by high phenotypic heterogeneity. The generation of heterogeneous myeloid populations endowed with tumor-promoting activities is typically promoted by growing tumors, indicating the sequential levels of myeloid reprogramming as possible antitumor targets. This work reviews the current knowledge on the events governing protumoral myelopoiesis, analyzing the mechanisms that drive the expansion of major myeloid subsets, as well as their functional properties, and highlighting recent translational strategies for clinical developments.
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50
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Pshennikova ES, Voronina AS. Dormancy: There and Back Again. Mol Biol 2022; 56:735-755. [PMID: 36217335 PMCID: PMC9534470 DOI: 10.1134/s0026893322050119] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 03/27/2022] [Accepted: 03/27/2022] [Indexed: 11/04/2022]
Abstract
Many cells are capable of maintaining viability in a non-dividing state with minimal metabolism under unfavorable conditions. These are germ cells, adult stem cells, and microorganisms. Unfortunately, a resting state, or dormancy, is possible for tuberculosis bacilli in a latent form of the disease and cancer cells, which may later form secondary tumors (metastases) in different parts of the body. These cells are resistant to therapy that can destroy intensely dividing cells and to the host immune system. A cascade of reactions that allows cells to enter and exit dormancy is triggered by regulatory factors from the microenvironment in niches that harbor the cells. A ratio of forbidding and permitting signals dictates whether the cells become dormant or start proliferation. The only difference between the cell dormancy regulation in normal and pathological conditions is that pathogens, mycobacteria, and cancer cells can influence their own fate by changing their microenvironment. Certain mechanisms of these processes are considered in the review.
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Affiliation(s)
- E. S. Pshennikova
- Bakh Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia
| | - A. S. Voronina
- Bakh Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia
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