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Hashemi SS, Alizadeh R, Rafati A, Mohammadi A, Mortazavi M, Hashempur MH. Investigation of silicon oxide nanoparticle-enhanced self-healing hydrogel for cartilage repair and regeneration in rabbit earlobe models. J Drug Target 2025:1-13. [PMID: 40019486 DOI: 10.1080/1061186x.2025.2473675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 02/12/2025] [Accepted: 02/23/2025] [Indexed: 03/01/2025]
Abstract
This study developed an alginate, gelatine and chondroitin sulphate hydrogel incorporating silicon oxide nanoparticles to assess hydrogel morphology, cell proliferation and viability. The effectiveness of these hydrogels for cartilage repair was evaluated in vivo using male albino rabbits, divided into three groups: a control group without hydrogels, an observer group with hydrogels lacking nanoparticles and a treatment group with nanoparticle-enhanced hydrogels for post-injury repair. At 15, 30 and 60 days post-surgery, the rabbits were humanely euthanized and excised tissue samples were fixed in 10% formalin for histopathological analysis, then processed and embedded in paraffin for microscopic evaluation. Statistical analysis was performed using SPSS software with ANOVA and Tukey's post hoc test. Results indicated that the hydrogels supported cell viability and encouraged differentiation into chondrocyte-like phenotypes. Scanning electron microscopy confirmed the hydrogels' porosity and showed significant differences in cell survival rates compared to the control group, underscoring the potential of hydrogels in cartilage tissue engineering and regenerative repair strategies.
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Affiliation(s)
- Seyedeh-Sara Hashemi
- Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Alizadeh
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Rafati
- Division of Pharmacology and Pharmaceutical Chemistry, Sarvestan Branch, Islamic Azad University, Sarvestan, Iran
| | - Aliakbar Mohammadi
- Burn and Wound Healing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mojtaba Mortazavi
- Department of Biotechnology, Institute of Science and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman, Iran
| | - Mohammad Hashem Hashempur
- Research Center for Traditional Medicine and History of Medicine, Department of Persian Medicine, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Shirdare M, Amiri F, Samiee MP, Safari A. Influential factors for optimizing and strengthening mesenchymal stem cells and hematopoietic stem cells co-culture. Mol Biol Rep 2024; 51:189. [PMID: 38270694 DOI: 10.1007/s11033-023-09041-9] [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: 10/21/2022] [Accepted: 11/13/2023] [Indexed: 01/26/2024]
Abstract
Mesenchymal stem cells (MSCs) and Hematopoietic stem cells (HSCs) are two types of bone marrow stem cells that can proliferate and differentiate into different cell lineages. HSCs interact with MSCs under protective conditions, called niche. Numerous studies have indicated supportive effects of MSCs on HSCs proliferation and differentiation. Furthermore, HSCs have many clinical applications and could treat different hematologic and non-hematologic diseases. For this purpose, there is a need to perform in vitro studies to optimize their expansion. Therefore, various methods including co-culture with MSCs are used to address the limitations of HSCs culture. Some parameters that might be effective for improving the MSC/ HSC co-culture systems. Manipulating culture condition to enhance MSC paracrine activity, scaffolds, hypoxia, culture medium additives, and the use of various MSC sources, have been examined in different studies. In this article, we investigated the potential factors for optimizing HSCs/ MSCs co-culture. It might be helpful to apply a suitable approach for providing high-quality HSCs and improving their therapeutic applications.
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Affiliation(s)
- Mandana Shirdare
- Central Medical Laboratory, Vice Chancellor for Public Health, Hamadan University of Medical Science, Hamadan, Iran
| | - Fatemeh Amiri
- Department of Medical Laboratory Sciences, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| | - Mohammad Pouya Samiee
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Armita Safari
- Student Research Committee, Hamadan University of Medical Science, Hamadan, Iran
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Peng H, Lin Y, Hu F, Lv C, Wu B, Weng Q, Liu L, Xia C, Liu X, Zhao Y, Zhang Q, Geng Y, Zhang M, Wang J. Prolonged generation of multi-lineage blood cells in wild-type animals from pluripotent stem cells. Stem Cell Reports 2023; 18:720-735. [PMID: 36801005 PMCID: PMC10031304 DOI: 10.1016/j.stemcr.2023.01.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 01/19/2023] [Accepted: 01/19/2023] [Indexed: 02/18/2023] Open
Abstract
Regenerating prolonged multi-lineage hematopoiesis from pluripotent stem cells (PSCs), an unlimited cell source, is a crucial aim of regenerative hematology. In this study, we used a gene-edited PSC line and revealed that simultaneous expression of three transcription factors, Runx1, Hoxa9, and Hoxa10, drove the robust emergence of induced hematopoietic progenitor cells (iHPCs). The iHPCs engrafted successfully in wild-type animals and repopulated abundant and complete myeloid-, B-, and T-lineage mature cells. The generative multi-lineage hematopoiesis distributed normally in multiple organs, persisted over 6 months, and eventually declined over time with no leukemogenesis. Transcriptome characterization of generative myeloid, B, and T cells at the single-cell resolution further projected their identities to natural cell counterparts. Thus, we provide evidence that co-expression of exogenous Runx1, Hoxa9, and Hoxa10 simultaneously leads to long-term reconstitution of myeloid, B, and T lineages using PSC-derived iHPCs as the cell source.
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Affiliation(s)
- Huan Peng
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yunqing Lin
- University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Fangxiao Hu
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100083, China
| | - Cui Lv
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
| | - Bingyan Wu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qitong Weng
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Lijuan Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Chengxiang Xia
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100083, China
| | - Xiaofei Liu
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yalan Zhao
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China
| | - Qi Zhang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yang Geng
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mengyun Zhang
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China.
| | - Jinyong Wang
- CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100083, China.
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4
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Hu Y, Huang J, Chen C, Wang Y, Hao Z, Chen T, Wang J, Li J. Strategies of Macrophages to Maintain Bone Homeostasis and Promote Bone Repair: A Narrative Review. J Funct Biomater 2022; 14:18. [PMID: 36662065 PMCID: PMC9864083 DOI: 10.3390/jfb14010018] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/17/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Bone homeostasis (a healthy bone mass) is regulated by maintaining a delicate balance between bone resorption and bone formation. The regulation of physiological bone remodeling by a complex system that involves multiple cells in the skeleton is closely related to bone homeostasis. Loss of bone mass or repair of bone is always accompanied by changes in bone homeostasis. However, due to the complexity of bone homeostasis, we are currently unable to identify all the mechanisms that affect bone homeostasis. To date, bone macrophages have been considered a third cellular component in addition to osteogenic spectrum cells and osteoclasts. As confirmed by co-culture models or in vivo experiments, polarized or unpolarized macrophages interact with multiple components within the bone to ensure bone homeostasis. Different macrophage phenotypes are prone to resorption and formation of bone differently. This review comprehensively summarizes the mechanisms by which macrophages regulate bone homeostasis and concludes that macrophages can control bone homeostasis from osteoclasts, mesenchymal cells, osteoblasts, osteocytes, and the blood/vasculature system. The elaboration of these mechanisms in this narrative review facilitates the development of macrophage-based strategies for the treatment of bone metabolic diseases and bone defects.
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Affiliation(s)
- Yingkun Hu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Jinghuan Huang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200000, China
| | - Chunying Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Yi Wang
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Zhuowen Hao
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Tianhong Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Junwu Wang
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Jingfeng Li
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
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Oliveira CS, Nadine S, Gomes MC, Correia CR, Mano JF. Bioengineering the human bone marrow microenvironment in liquefied compartments: A promising approach for the recapitulation of osteovascular niches. Acta Biomater 2022; 149:167-178. [PMID: 35811072 DOI: 10.1016/j.actbio.2022.07.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 06/11/2022] [Accepted: 07/01/2022] [Indexed: 11/24/2022]
Abstract
Recreating the biological complexity of living bone marrow (BM) in a single in vitro strategy has faced many challenges. Most bioengineered strategies propose the co-culture of BM cellular components entrapped in different matrices limiting their migration and self-organization capacity or in open scaffolds enabling their escaping. We propose a methodology for fabricating a "human bone marrow-in-a-liquefied-capsule" to overcome these challenges, embracing the most important BM components in a single platform. Since free dispersion of the cells within the BM is an essential feature to maintain their in vivo properties, this platform provides a liquefied environment for the encapsulated cells to move freely and self-organize. Inside liquefied capsules, an engineered endosteal niche (eEN) is co-cultured with human umbilical cord cells, including endothelial cells and hematopoietic stem and progenitor cells (HSPCs). Two different human-like BM niches were recreated under static and dynamic systems. Although the culture of the engineered BM capsules (eBMC) in these different environments did not change the structural and compositional features of the BM niches, the biophysical stimulation potentiated the cellular intercommunication and the biomolecules secretion, demonstrating an enhanced in vitro bio performance. Moreover, while the eBMC without HSPCs provided the secretion of hematopoietic supportive factors, the presence of these cells recapitulated more closely the biological complexity of the native BM niches. This functional eBMC approach is an innovative platform capable of investigating several components and interactions of BM niches and how they regulate BM homeostasis and hematopoiesis. STATEMENT OF SIGNIFICANCE: The recapitulation of the multifaceted bone marrow (BM) microenvironment under in vitro conditions has gained intensive recognition to understand the intrinsic complexity of the native BM. While conventional strategies do not recapitulate the BM osteovascular niches nor give the cellular components a free movement, we report for the first time the development of human bone marrow-in-a-liquefied-capsule to overcome such limitations. Our engineered BM capsules (eBMC) partially mimic the complex structure, composition, and spatial organization of the native osteovascular niches present in the BM. This strategy offers a platform with physiological relevance to exploit the niches' components/networks and how they regulate the hematopoiesis and the initiation/progression of various BM-related pathologies.
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Affiliation(s)
- Cláudia S Oliveira
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
| | - Sara Nadine
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - Maria C Gomes
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - Clara R Correia
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - João F Mano
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
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Nandakumar N, Mohan M, Thilakan AT, Sidharthan HK, Janarthanan R, Sharma D, Nair SV, Sathy BN. Bioengineered 3D microfibrous-matrix modulates osteopontin release from MSCs and facilitates the expansion of hematopoietic stem cells. Biotechnol Bioeng 2022; 119:2964-2978. [PMID: 35799309 DOI: 10.1002/bit.28175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 06/29/2022] [Accepted: 07/05/2022] [Indexed: 11/10/2022]
Abstract
The osteopontin released from mesenchymal stem cells (MSC) undergoing lineage differentiation can negatively influence the expansion of hematopoietic stem cells (HSCs) in co-culture systems developed for expanding HSCs. Therefore, minimising the amount of osteopontin in the co-culture system is important for the successful ex vivo expansion of HSCs. Towards this goal, a bioengineered 3D microfibrous-matrix that can maintain MSCs in less osteopontin-releasing conditions has been developed, and its influence on the expansion of HSCs has been studied. The newly developed 3D matrix significantly decreased the release of osteopontin, depending on the MSC culture conditions used during the priming period before HSC seeding. The culture system with the lowest amount of osteopontin facilitated a more than 24-fold increase in HSC number in 1 week time period. Interestingly, the viability of expanded cells and the CD34+ pure population of HSCs were found to be the highest in the low osteopontin-containing system. Therefore, bioengineered microfibrous 3D matrices seeded with MSCs, primed under suitable culture conditions, can be an improved ex vivo expansion system for HSC culture. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Niji Nandakumar
- Amrita Center for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Malini Mohan
- Amrita Center for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Akhil T Thilakan
- Amrita Center for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Hridhya K Sidharthan
- Amrita Center for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - R Janarthanan
- Centre for Plastic and Reconstructive Surgery, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Deepti Sharma
- Department of Obstetrics and Gynaecology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Shantikumar V Nair
- Amrita Center for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Binulal N Sathy
- Amrita Center for Nanosciences and Molecular Medicine, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
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Atmar K, Tulling AJ, Lankester AC, Bartels M, Smiers FJ, van der Burg M, Mohseny AB. Functional and Immune Modulatory Characteristics of Bone Marrow Mesenchymal Stromal Cells in Patients With Aplastic Anemia: A Systematic Review. Front Immunol 2022; 13:859668. [PMID: 35355996 PMCID: PMC8959635 DOI: 10.3389/fimmu.2022.859668] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 02/17/2022] [Indexed: 11/13/2022] Open
Abstract
Background In most patients with aplastic anemia (AA), the diagnosis is limited to a description of the symptoms. Lack of understanding of the underlying pathophysiological mechanisms causing bone marrow failure (BMF), hampers tailored treatment. In these patients, auto-immune cell-mediated destruction of the bone marrow is often presumed to be the causative mechanism. The status of the bone marrow microenvironment, particularly the mesenchymal stromal cell (MSC) component, was recently suggested as a potential player in the pathophysiology of AA. Therefore, functional, and immune modulatory characteristics of bone marrow MSCs might represent important parameters for AA. Objective To conduct a systematic review to evaluate in vitro functional properties of MSCs derived from patients with AA compared to healthy controls. Methods According to PRISMA guidelines, a comprehensive search strategy was performed by using online databases (Pubmed, ISI Web of Science, Embase, and the Cochrane Library). Studies reporting on phenotypical characterization, proliferation potential, differentiation capacity, immunomodulatory potential, and ability to support hematopoiesis were identified and screened using the Rayyan software tool. Results 23 articles were included in this systematic review, describing a total of 324 patients with AA and 285 controls. None of the studies identified a significant difference in expression of any MSC surface marker between both groups. However, AA-MSCs showed a decreased proliferation potential, an increased tendency to differentiate into the adipogenic lineage and decreased propensity towards osteogenic differentiation. Importantly, AA-MSCs show reduced capacity of immunosuppression and hematopoietic support in comparison to healthy controls. Conclusion We conclude that there are indications for a contribution of MSCs in the pathophysiology of AA. However, the current evidence is of poor quality and requires better defined study populations in addition to a more robust methodology to study MSC biology at a cellular and molecular level. Future studies on bone marrow microenvironment should aim at elucidating the interaction between MSCs, hematopoietic stem cells (HSCs) and immune cells to identify impairments associated with/causing BMF in patients with AA.
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Affiliation(s)
- Khaled Atmar
- Department of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands
| | - Adam J Tulling
- Department of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands
| | - Arjan C Lankester
- Department of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands
| | - Marije Bartels
- Department of Pediatric Hematology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, Netherlands
| | - Frans J Smiers
- Department of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands
| | - Mirjam van der Burg
- Laboratory for Pediatric Immunology, Department of Pediatrics, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands
| | - Alexander B Mohseny
- Department of Pediatric Hematology and Stem Cell Transplantation, Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands
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Gilchrist AE, Harley BA. Engineered Tissue Models to Replicate Dynamic Interactions within the Hematopoietic Stem Cell Niche. Adv Healthc Mater 2022; 11:e2102130. [PMID: 34936239 PMCID: PMC8986554 DOI: 10.1002/adhm.202102130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/19/2021] [Indexed: 12/19/2022]
Abstract
Hematopoietic stem cells are the progenitors of the blood and immune system and represent the most widely used regenerative therapy. However, their rarity and limited donor base necessitate the design of ex vivo systems that support HSC expansion without the loss of long-term stem cell activity. This review describes recent advances in biomaterials systems to replicate features of the hematopoietic niche. Inspired by the native bone marrow, these instructive biomaterials provide stimuli and cues from cocultured niche-associated cells to support HSC encapsulation and expansion. Engineered systems increasingly enable study of the dynamic nature of the matrix and biomolecular environment as well as the role of cell-cell signaling (e.g., autocrine feedback vs paracrine signaling between dissimilar cells). The inherent coupling of material properties, biotransport of cell-secreted factors, and cell-mediated remodeling motivate dynamic biomaterial systems as well as characterization and modeling tools capable of evaluating a temporally evolving tissue microenvironment. Recent advances in HSC identification and tracking, model-based experimental design, and single-cell culture platforms facilitate the study of the effect of constellations of matrix, cell, and soluble factor signals on HSC fate. While inspired by the HSC niche, these tools are amenable to the broader stem cell engineering community.
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Affiliation(s)
- Aidan E. Gilchrist
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Brendan A.C. Harley
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL 61801
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Wang J, Xiong M, Sun Q, Tan WS, Cai H. Three-Dimension Co-culture of Hematopoietic Stem Cells and Differentiated Osteoblasts on Gallic Acid Grafted-Chitosan Scaffold as a Model of Hematopoietic Stem Cells Niche. Stem Cell Rev Rep 2022; 18:1168-1180. [PMID: 34985623 DOI: 10.1007/s12015-021-10325-5] [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] [Accepted: 12/28/2021] [Indexed: 11/26/2022]
Abstract
The existing approaches of hematopoietic stem cells (HSCs) expansion in vitro were difficult to meet the needs of clinical application. While in vivo, HSCs efficiently self-renew in niche where they interact with three dimension extracellular matrix and stromal cells. Osteoblasts (OBs) are one of most significant stromal cells of HSCs niche. Here, we proposed a three-dimensional environment based on gallic acid grafted-chitosan (2c) scaffold and OBs differentiated from human umbilical cord mesenchymal stem cells (HUMSCs) to recapitulate the main components of HSCs niche. The results of alkaline phosphatase staining and alizarin red staining demonstrated that HUMSCs were successfully induced into OBs. The results showed that the expansions of CD34+cells, CD34+CD38- cells and CD34+CD38-CD45RA-CD49f+CD90+ cells (primitive hematopoietic stem cells, pHSCs) harvested from the biomimetic HSCs niche based on 2c scaffold and OBs (IV) group were larger than those harvested from other three culture groups. Importantly, it was found that the CD34+ cells harvested from IV group had better secondary expansion capability and colony forming potential, indicating better self-renewal ability. In addition, the biomimetic HSCs niche based on 2c scaffold and OBs protected HSCs apoptosis and promoted HSCs division. Taken together, the biomimetic HSCs niche based on 2c scaffold and OBs was an effective strategy for ex vivo expansion of HSCs in clinical scale.
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Affiliation(s)
- Jin Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Minghao Xiong
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Qihao Sun
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Wen-Song Tan
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Haibo Cai
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.
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10
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Oliveira CS, Leeuwenburgh S, Mano JF. New insights into the biomimetic design and biomedical applications of bioengineered bone microenvironments. APL Bioeng 2021; 5:041507. [PMID: 34765857 PMCID: PMC8568480 DOI: 10.1063/5.0065152] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/06/2021] [Indexed: 12/31/2022] Open
Abstract
The bone microenvironment is characterized by an intricate interplay between cellular and noncellular components, which controls bone remodeling and repair. Its highly hierarchical architecture and dynamic composition provide a unique microenvironment as source of inspiration for the design of a wide variety of bone tissue engineering strategies. To overcome current limitations associated with the gold standard for the treatment of bone fractures and defects, bioengineered bone microenvironments have the potential to orchestrate the process of bone regeneration in a self-regulated manner. However, successful approaches require a strategic combination of osteogenic, vasculogenic, and immunomodulatory factors through a synergic coordination between bone cells, bone-forming factors, and biomaterials. Herein, we provide an overview of (i) current three-dimensional strategies that mimic the bone microenvironment and (ii) potential applications of bioengineered microenvironments. These strategies range from simple to highly complex, aiming to recreate the architecture and spatial organization of cell-cell, cell-matrix, and cell-soluble factor interactions resembling the in vivo microenvironment. While several bone microenvironment-mimicking strategies with biophysical and biochemical cues have been proposed, approaches that exploit the ability of the cells to self-organize into microenvironments with a high regenerative capacity should become a top priority in the design of strategies toward bone regeneration. These miniaturized bone platforms may recapitulate key characteristics of the bone regenerative process and hold great promise to provide new treatment concepts for the next generation of bone implants.
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Affiliation(s)
- Cláudia S. Oliveira
- Department of Chemistry, CICECO–Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - Sander Leeuwenburgh
- Department of Dentistry-Regenerative Biomaterials, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Philips van Leydenlaan 25, 6525 EX Nijmegen, The Netherlands
| | - João F. Mano
- Department of Chemistry, CICECO–Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
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Amiri F, Kiani AA, Bahadori M, Roudkenar MH. Co-culture of mesenchymal stem cell spheres with hematopoietic stem cells under hypoxia: a cost-effective method to maintain self-renewal and homing marker expression. Mol Biol Rep 2021; 49:931-941. [PMID: 34741711 DOI: 10.1007/s11033-021-06912-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 10/29/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Hematopoietic stem cell (HSC) transplantation is considered a possible treatment option capable of curing various diseases. The aim of this study was the co-culturing of mesenchymal stem cell (MSC) spheres with HSCs under hypoxic condition to enhance the proliferation, self-renewal, stemness, and homing capacities of HSCs. METHODS AND RESULTS HSCs were expanded after being subjected to different conditions including cytokines without feeder (Cyto), co-culturing with adherent MSCs (MSC), co-culturing with adherent MSCs + hypoxia (MSC + Hyp), co-culturing with MSCs spheres (Sph-MSC), co-culturing with MSCs spheres + hypoxia (Sph-MSC + Hyp), co-culturing with MSC spheres + cytokines (Sph-MSC + Cyto). After 10 days, total nucleated cell (TNC) and CD34+/CD38- cell counts, colony-forming unit assay (CFU), long-term culture initiating cell (LTC-IC), the expression of endothelial protein C receptor (EPCR), nucleostemin (NS), nuclear factor I/X (Nfix) CXCR4, and VLA-4 were evaluated. The TNC, CD34+/CD38- cell count, CFU, and LTC-IC were higher in the Sph-MSC + Hyp and Sph-MSC + Cyto groups as compared with those of the MSC + Hyp group (P < 0.001). The expanded HSCs co-cultured with MSC spheres in combination with hypoxia expressed more EPCR, CXCR4, VLA-4, NS, and Nfix mRNA. The protein expression was also more up-regulated in the Sph-MSC + Cyto and Sph-MSC + Hyp groups. CONCLUSION Co-culturing HSCs with MSC spheres under hypoxic condition not only leads to higher cellular yield but also increases the expression of self-renewal and homing genes. Therefore, we suggest this approach as a simple and non-expensive strategy that might improve the transplantation efficiency of HSCs.
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Affiliation(s)
- Fatemeh Amiri
- Department of Medical Laboratory Sciences, School of Para Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Ali Asghar Kiani
- Department of Hematology and Blood Transfusion, Lorestan University of Medical Sciences, Khorramabad, Lorestan, Iran
| | - Marzie Bahadori
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Mehryar Habibi Roudkenar
- Cardiovascular Diseases Research Center, Department of Cardiology, Heshmat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran. .,Burn and Regenerative Research Center, Guilan University of Medical Sciences, Rasht, Iran.
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12
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Rebuilding the hematopoietic stem cell niche: Recent developments and future prospects. Acta Biomater 2021; 132:129-148. [PMID: 33813090 DOI: 10.1016/j.actbio.2021.03.061] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 03/25/2021] [Accepted: 03/25/2021] [Indexed: 12/20/2022]
Abstract
Hematopoietic stem cells (HSCs) have proven their clinical relevance in stem cell transplantation to cure patients with hematological disorders. Key to their regenerative potential is their natural microenvironment - their niche - in the bone marrow (BM). Developments in the field of biomaterials enable the recreation of such environments with increasing preciseness in the laboratory. Such artificial niches help to gain a fundamental understanding of the biophysical and biochemical processes underlying the interaction of HSCs with the materials in their environment and the disturbance of this interplay during diseases affecting the BM. Artificial niches also have the potential to multiply HSCs in vitro, to enable the targeted differentiation of HSCs into mature blood cells or to serve as drug-testing platforms. In this review, we will introduce the importance of artificial niches followed by the biology and biophysics of the natural archetype. We will outline how 2D biomaterials can be used to dissect the complexity of the natural niche into individual parameters for fundamental research and how 3D systems evolved from them. We will present commonly used biomaterials for HSC research and their applications. Finally, we will highlight two areas in the field of HSC research, which just started to unlock the possibilities provided by novel biomaterials, in vitro blood production and studying the pathophysiology of the niche in vitro. With these contents, the review aims to give a broad overview of the different biomaterials applied for HSC research and to discuss their potentials, challenges and future directions in the field. STATEMENT OF SIGNIFICANCE: Hematopoietic stem cells (HSCs) are multipotent cells responsible for maintaining the turnover of all blood cells. They are routinely applied to treat patients with hematological diseases. This high clinical relevance explains the necessity of multiplication or differentiation of HSCs in the laboratory, which is hampered by the missing natural microenvironment - the so called niche. Biomaterials offer the possibility to mimic the niche and thus overcome this hurdle. The review introduces the HSC niche in the bone marrow and discusses the utility of biomaterials in creating artificial niches. It outlines how 2D systems evolved into sophisticated 3D platforms, which opened the gateway to applications such as, expansion of clinically relevant HSCs, in vitro blood production, studying niche pathologies and drug testing.
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13
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Wu Y, Zhang Q, Zhao B, Wang X. Effect and mechanism of propranolol on promoting osteogenic differentiation and early implant osseointegration. Int J Mol Med 2021; 48:191. [PMID: 34414453 PMCID: PMC8416142 DOI: 10.3892/ijmm.2021.5024] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 06/09/2021] [Indexed: 12/17/2022] Open
Abstract
The present study aimed to investigate the effect of β‑receptor blocker propranolol on early osseointegration of pure titanium implants and the underlying molecular regulatory mechanisms. An implant osseointegration model using the tibial metaphysis of New Zealand rabbits was established. The rabbits were divided into control and low‑, medium‑ and high‑dose propranolol groups. The formation of implant osseointegration was detected by X‑ray scanning. Mesenchymal stem cells (MSCs) and osteoblasts (OBs) were isolated and cultured in vitro, isoproterenol was supplemented to simulate sympathetic action and propranolol was subsequently administrated. The effect of propranolol on cell proliferation and osteogenic differentiation were assessed by EdU, flow cytometry, alizarin red staining and alkaline phosphatase (ALP) detection. The expression levels of bone morphogenetic protein (BMP)2, RUNX family transcription factor (RunX)2, collagen (COL)‑1, osteocalcin (OCN) and β2‑adrenergic receptor (AR) were detected by immunofluorescence, reverse transcription‑quantitative PCR and western blot assay. Propranolol effectively promoted implant osseointegration in vivo, facilitated proliferation of OBs, inhibited proliferation of MSCs and enhanced osteogenic differentiation of OBs and MSCs. The calcium content and ALP activity of cells treated with propranolol were markedly higher than in the control group. Propranolol also elevated mRNA and protein expression levels of BMP2, RunX2, COL‑1 and OCN in tissue and cells, and decreased the expression of β2‑AR. The present study demonstrated that the β‑receptor blocker propranolol promoted osteogenic differentiation of OBs and MSCs and enhanced implant osseointegration. The present study provided a novel insight into the application and regulatory mechanisms of propranolol.
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Affiliation(s)
- Yupeng Wu
- Department of Oral Implantology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Qi Zhang
- School of Stomatology, Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Baodong Zhao
- Department of Oral Implantology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
| | - Xiaojing Wang
- Department of Oral Implantology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, P.R. China
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14
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Kronstein-Wiedemann R, Thiel J, Tonn T. Blood Pharming – eine realistische Option? TRANSFUSIONSMEDIZIN 2021. [DOI: 10.1055/a-1342-0820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
ZusammenfassungDie Bluttransfusion ist ein wesentlicher und unersetzlicher Teil der modernen Medizin. Jedoch stellt vor allem bei Patienten mit sehr seltenen Blutgruppenkonstellationen der Mangel an Blutprodukten auch heute noch ein wichtiges Gesundheitsproblem weltweit dar. Um diesem Problem entgegenzutreten, versucht man seit einiger Zeit künstlich rote Blutzellen zu generieren. Diese haben potenzielle Vorteile gegenüber Spenderblut, wie z. B. ein verringertes Risiko für die Übertragung von Infektionskrankheiten. Diese Übersicht fasst die aktuellen Entwicklungen über den Prozess der Erythropoese, die Expansionsstrategien der erythrozytären Zellen, der verschiedenen Quellen für ex vivo expandierte Erythrozyten, die Hürden für die klinische Anwendung und die zukünftigen Möglichkeiten der Anwendung zusammen.
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Affiliation(s)
- Romy Kronstein-Wiedemann
- DRK-Blutspendedienst Nord-Ost gGmbH/Institut Dresden
- Experimentelle Transfusionsmedizin, Medizinische Fakultät Universitätsklinikum Carl Gustav Carus
| | - Jessica Thiel
- DRK-Blutspendedienst Nord-Ost gGmbH/Institut Dresden
- Experimentelle Transfusionsmedizin, Medizinische Fakultät Universitätsklinikum Carl Gustav Carus
| | - Torsten Tonn
- DRK-Blutspendedienst Nord-Ost gGmbH/Institut Dresden
- Experimentelle Transfusionsmedizin, Medizinische Fakultät Universitätsklinikum Carl Gustav Carus
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15
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Crippa S, Santi L, Berti M, De Ponti G, Bernardo ME. Role of ex vivo Expanded Mesenchymal Stromal Cells in Determining Hematopoietic Stem Cell Transplantation Outcome. Front Cell Dev Biol 2021; 9:663316. [PMID: 34017834 PMCID: PMC8129582 DOI: 10.3389/fcell.2021.663316] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 03/17/2021] [Indexed: 02/06/2023] Open
Abstract
Overall, the human organism requires the production of ∼1 trillion new blood cells per day. Such goal is achieved via hematopoiesis occurring within the bone marrow (BM) under the tight regulation of hematopoietic stem and progenitor cell (HSPC) homeostasis made by the BM microenvironment. The BM niche is defined by the close interactions of HSPCs and non-hematopoietic cells of different origin, which control the maintenance of HSPCs and orchestrate hematopoiesis in response to the body’s requirements. The activity of the BM niche is regulated by specific signaling pathways in physiological conditions and in case of stress, including the one induced by the HSPC transplantation (HSCT) procedures. HSCT is the curative option for several hematological and non-hematological diseases, despite being associated with early and late complications, mainly due to a low level of HSPC engraftment, impaired hematopoietic recovery, immune-mediated graft rejection, and graft-versus-host disease (GvHD) in case of allogenic transplant. Mesenchymal stromal cells (MSCs) are key elements of the BM niche, regulating HSPC homeostasis by direct contact and secreting several paracrine factors. In this review, we will explore the several mechanisms through which MSCs impact on the supportive activity of the BM niche and regulate HSPC homeostasis. We will further discuss how the growing understanding of such mechanisms have impacted, under a clinical point of view, on the transplantation field. In more recent years, these results have instructed the design of clinical trials to ameliorate the outcome of HSCT, especially in the allogenic setting, and when low doses of HSPCs were available for transplantation.
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Affiliation(s)
- Stefania Crippa
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Ludovica Santi
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Margherita Berti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giada De Ponti
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy
| | - Maria Ester Bernardo
- San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy.,Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy.,University Vita-Salute San Raffaele, Faculty of Medicine, Milan, Italy
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16
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Oliveira CS, Carreira M, Correia CR, Mano JF. The Therapeutic Potential of Hematopoietic Stem Cells in Bone Regeneration. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:379-392. [PMID: 33683146 DOI: 10.1089/ten.teb.2021.0019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The repair process of bone fractures is a complex biological mechanism requiring the recruitment and in situ functionality of stem/stromal cells from the bone marrow (BM). BM mesenchymal stem/stromal cells have been widely explored in multiple bone tissue engineering applications, whereas the use of hematopoietic stem cells (HSCs) has been poorly investigated in this context. A reasonable explanation is the fact that the role of HSCs and their combined effect with other elements of the hematopoietic niches in the bone-healing process is still elusive. Therefore, in this review we intend to highlight the influence of HSCs in the bone repair process, mainly through the promotion of osteogenesis and angiogenesis at the bone injury site. For that, we briefly describe the main biological characteristics of HSCs, as well as their hematopoietic niches, while reviewing the biomimetic engineered BM niche models. Moreover, we also highlighted the role of HSCs in translational in vivo transplantation or implantation as promoters of bone tissue repair.
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Affiliation(s)
- Cláudia S Oliveira
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - Mariana Carreira
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - Clara R Correia
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
| | - João F Mano
- Department of Chemistry, CICECO-Aveiro Institute of Materials, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal
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17
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Kim H, Han SH, Kook YM, Lee KM, Jin YZ, Koh WG, Lee JH, Lee K. A novel 3D indirect co-culture system based on a collagen hydrogel scaffold for enhancing the osteogenesis of stem cells. J Mater Chem B 2021; 8:9481-9491. [PMID: 32996551 DOI: 10.1039/d0tb01770a] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In this study, the paracrine effect between adipose-derived mesenchymal stem cells (ADSCs) and osteoblasts was investigated in collagen-based three-dimensional (3D) scaffolds. 3D encapsulation of mesenchymal stem cells in hydrogel scaffolds was conducted for bone tissue regeneration. Osteoblasts were encapsulated in alginate microbeads with uniform size, which could be controlled by varying the supply voltage using electrostatic droplet extrusion. Osteoblast-encapsulated microbeads were embedded with ADSCs in collagen bulk hydrogel scaffolds with a high survival rate. The separated space between the two types of cells made it possible to confirm ADSC differentiation into osteogenic lineages in the 3D collagen hydrogel scaffold by the paracrine effect in vitro. Furthermore, co-cultured ADSC and osteoblasts showed enhanced bone formation compared with the ADSC monoculture group in the rat calvarial defect model. The system developed in this study provides a novel in vitro tissue model for bone regeneration without exogenous factors, and it has the potential to be used to study the paracrine effect in various co-culture systems in the near future.
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Affiliation(s)
- Hyerim Kim
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
| | - Shi Huan Han
- Department of Orthopedic Surgery, College of Medicine, Seoul National University, Seoul, 03080, Korea. and Department of Orthopedic Surgery, YanBian University Hospital, 133000, Yanji, Jilin Province, China
| | - Yun-Min Kook
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Korea
| | - Kyung-Mee Lee
- Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, Seoul, 07061, Korea
| | - Yuan-Zhe Jin
- Department of Spine Surgery, The First Hospital of Jilin University, 130021, Changchun, Jilin Province, China
| | - Won-Gun Koh
- Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul, Korea.
| | - Jae Hyup Lee
- Department of Orthopedic Surgery, College of Medicine, Seoul National University, Seoul, 03080, Korea. and Department of Orthopedic Surgery, SMG-SNU Boramae Medical Center, Seoul, 07061, Korea and Institute of Medical and Biological Engineering, Seoul National University, Seoul, 110-799, Korea
| | - Kangwon Lee
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea.
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18
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Leguit RJ, Raymakers RAP, Hebeda KM, Goldschmeding R. CCN2 (Cellular Communication Network factor 2) in the bone marrow microenvironment, normal and malignant hematopoiesis. J Cell Commun Signal 2021; 15:25-56. [PMID: 33428075 PMCID: PMC7798015 DOI: 10.1007/s12079-020-00602-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Accepted: 12/20/2020] [Indexed: 02/06/2023] Open
Abstract
CCN2, formerly termed Connective Tissue Growth Factor, is a protein belonging to the Cellular Communication Network (CCN)-family of secreted extracellular matrix-associated proteins. As a matricellular protein it is mainly considered to be active as a modifier of signaling activity of several different signaling pathways and as an orchestrator of their cross-talk. Furthermore, CCN2 and its fragments have been implicated in the regulation of a multitude of biological processes, including cell proliferation, differentiation, adhesion, migration, cell survival, apoptosis and the production of extracellular matrix products, as well as in more complex processes such as embryonic development, angiogenesis, chondrogenesis, osteogenesis, fibrosis, mechanotransduction and inflammation. Its function is complex and context dependent, depending on cell type, state of differentiation and microenvironmental context. CCN2 plays a role in many diseases, especially those associated with fibrosis, but has also been implicated in many different forms of cancer. In the bone marrow (BM), CCN2 is highly expressed in mesenchymal stem/stromal cells (MSCs). CCN2 is important for MSC function, supporting its proliferation, migration and differentiation. In addition, stromal CCN2 supports the maintenance and longtime survival of hematopoietic stem cells, and in the presence of interleukin 7, stimulates the differentiation of pro-B lymphocytes into pre-B lymphocytes. Overexpression of CCN2 is seen in the majority of B-acute lymphoblastic leukemias, especially in certain cytogenetic subgroups associated with poor outcome. In acute myeloid leukemia, CCN2 expression is increased in MSCs, which has been associated with leukemic engraftment in vivo. In this review, the complex function of CCN2 in the BM microenvironment and in normal as well as malignant hematopoiesis is discussed. In addition, an overview is given of data on the remaining CCN family members regarding normal and malignant hematopoiesis, having many similarities and some differences in their function.
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Affiliation(s)
- Roos J. Leguit
- Department of Pathology, University Medical Center Utrecht, H04-312, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
| | - Reinier A. P. Raymakers
- Department of Hematology, UMCU Cancer Center, Heidelberglaan 100 B02.226, 3584 CX Utrecht, The Netherlands
| | - Konnie M. Hebeda
- Department of Pathology, Radboud University Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Roel Goldschmeding
- Department of Pathology, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands
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19
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3D Scaffolds to Model the Hematopoietic Stem Cell Niche: Applications and Perspectives. MATERIALS 2021; 14:ma14030569. [PMID: 33530372 PMCID: PMC7865713 DOI: 10.3390/ma14030569] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 12/19/2022]
Abstract
Hematopoietic stem cells (HSC) are responsible for the production of blood and immune cells during life. HSC fate decisions are dependent on signals from specialized microenvironments in the bone marrow, termed niches. The HSC niche is a tridimensional environment that comprises cellular, chemical, and physical elements. Introductorily, we will revise the current knowledge of some relevant elements of the niche. Despite the importance of the niche in HSC function, most experimental approaches to study human HSCs use bidimensional models. Probably, this contributes to the failure in translating many in vitro findings into a clinical setting. Recreating the complexity of the bone marrow microenvironment in vitro would provide a powerful tool to achieve in vitro production of HSCs for transplantation, develop more effective therapies for hematologic malignancies and provide deeper insight into the HSC niche. We previously demonstrated that an optimized decellularization method can preserve with striking detail the ECM architecture of the bone marrow niche and support HSC culture. We will discuss the potential of this decellularized scaffold as HSC niche model. Besides decellularized scaffolds, several other methods have been reported to mimic some characteristics of the HSC niche. In this review, we will examine these models and their applications, advantages, and limitations.
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20
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Janagama D, Hui SK. 3-D Cell Culture Systems in Bone Marrow Tissue and Organoid Engineering, and BM Phantoms as In Vitro Models of Hematological Cancer Therapeutics-A Review. MATERIALS 2020; 13:ma13245609. [PMID: 33316977 PMCID: PMC7763362 DOI: 10.3390/ma13245609] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 10/24/2020] [Accepted: 10/29/2020] [Indexed: 12/15/2022]
Abstract
We review the state-of-the-art in bone and marrow tissue engineering (BMTE) and hematological cancer tissue engineering (HCTE) in light of the recent interest in bone marrow environment and pathophysiology of hematological cancers. This review focuses on engineered BM tissue and organoids as in vitro models of hematological cancer therapeutics, along with identification of BM components and their integration as synthetically engineered BM mimetic scaffolds. In addition, the review details interaction dynamics of various BM and hematologic cancer (HC) cell types in co-culture systems of engineered BM tissues/phantoms as well as their relation to drug resistance and cytotoxicity. Interaction between hematological cancer cells and their niche, and the difference with respect to the healthy niche microenvironment narrated. Future perspectives of BMTE for in vitro disease models, BM regeneration and large scale ex vivo expansion of hematopoietic and mesenchymal stem cells for transplantation and therapy are explained. We conclude by overviewing the clinical application of biomaterials in BM and HC pathophysiology and its challenges and opportunities.
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21
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An Overview of Different Strategies to Recreate the Physiological Environment in Experimental Erythropoiesis. Int J Mol Sci 2020; 21:ijms21155263. [PMID: 32722249 PMCID: PMC7432157 DOI: 10.3390/ijms21155263] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 12/19/2022] Open
Abstract
Human erythropoiesis is a complex process leading to the production of mature, enucleated erythrocytes (RBCs). It occurs mainly at bone marrow (BM), where hematopoietic stem cells (HSCs) are engaged in the early erythroid differentiation to commit into erythroid progenitor cells (burst-forming unit erythroid (BFU-E) and colony-forming unit erythroid (CFU-E)). Then, during the terminal differentiation, several erythropoietin-induced signaling pathways trigger the differentiation of CFU-E on successive stages from pro-erythroblast to reticulocytes. The latter are released into the circulation, finalizing their maturation into functional RBCs. This process is finely regulated by the physiological environment including the erythroblast-macrophage interaction in the erythroblastic island (EBI). Several human diseases have been associated with ineffective erythropoiesis, either by a defective or an excessive production of RBCs, as well as an increase or a hemoglobinization defect. Fully understanding the production of mature red blood cells is crucial for the comprehension of erythroid pathologies as well as to the field of transfusion. Many experimental approaches have been carried out to achieve a complete differentiation in vitro to produce functional biconcave mature RBCs. However, the various protocols usually fail to achieve enough quantities of completely mature RBCs. In this review, we focus on the evolution of erythropoiesis studies over the years, taking special interest in efforts that were made to include the microenvironment and erythroblastic islands paradigm. These more physiological approaches will contribute to a deeper comprehension of erythropoiesis, improve the treatment of dyserythropoietic disorders, and break through the barriers in massive RBCs production for transfusion.
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22
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Wong SW, Lenzini S, Cooper MH, Mooney DJ, Shin JW. Soft extracellular matrix enhances inflammatory activation of mesenchymal stromal cells to induce monocyte production and trafficking. SCIENCE ADVANCES 2020; 6:eaaw0158. [PMID: 32284989 PMCID: PMC7141831 DOI: 10.1126/sciadv.aaw0158] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 01/14/2020] [Indexed: 05/17/2023]
Abstract
Mesenchymal stromal cells (MSCs) modulate immune cells to ameliorate multiple inflammatory pathologies. Biophysical signals that regulate this process are poorly defined. By engineering hydrogels with tunable biophysical parameters relevant to bone marrow where MSCs naturally reside, we show that soft extracellular matrix maximizes the ability of MSCs to produce paracrine factors that have been implicated in monocyte production and chemotaxis upon inflammatory stimulation by tumor necrosis factor-α (TNFα). Soft matrix increases clustering of TNF receptors, thereby enhancing NF-κB activation and downstream gene expression. Actin polymerization and lipid rafts, but not myosin-II contractility, regulate mechanosensitive activation of MSCs by TNFα. We functionally demonstrate that human MSCs primed with TNFα in soft matrix enhance production of human monocytes in marrow of xenografted mice and increase trafficking of monocytes via CCL2. The results suggest the importance of biophysical signaling in tuning inflammatory activation of stromal cells to control the innate immune system.
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Affiliation(s)
- Sing Wan Wong
- Department of Pharmacology and Department of Bioengineering, University of Illinois at Chicago College of Medicine, Chicago, IL, USA
| | - Stephen Lenzini
- Department of Pharmacology and Department of Bioengineering, University of Illinois at Chicago College of Medicine, Chicago, IL, USA
| | - Madeline H. Cooper
- School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
| | - David J. Mooney
- School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA
| | - Jae-Won Shin
- Department of Pharmacology and Department of Bioengineering, University of Illinois at Chicago College of Medicine, Chicago, IL, USA
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23
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Akbari A, Jabbari N, Sharifi R, Ahmadi M, Vahhabi A, Seyedzadeh SJ, Nawaz M, Szafert S, Mahmoodi M, Jabbari E, Asghari R, Rezaie J. Free and hydrogel encapsulated exosome-based therapies in regenerative medicine. Life Sci 2020; 249:117447. [PMID: 32087234 DOI: 10.1016/j.lfs.2020.117447] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/09/2020] [Accepted: 02/17/2020] [Indexed: 12/21/2022]
Abstract
Over the last few decades, mesenchymal stem cells-derived exosomes (MSCs-Ex) have attracted a lot of attention as a therapeutic tool in regenerative medicine. Exosomes are extracellular vehicles (EVs) that play important roles in cell-cell communication through various processes such as stress response, senescence, angiogenesis, and cell differentiation. Success in the field of regenerative medicine sparked exploration of the potential use of exosomes as key therapeutic effectors of MSCs to promote tissue regeneration. Various approaches including direct injection, intravenous injection, intraperitoneal injection, oral administration, and hydrogel-based encapsulation have been exploited to deliver exosomes to target tissues in different disease models. Despite significant advances in exosome therapy, it is unclear which approach is more effective for administering exosomes. Herein, we critically review the emerging progress in the applications of exosomes in the form of free or association with hydrogels as therapeutic agents for applications in regenerative medicine.
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Affiliation(s)
- Ali Akbari
- Solid Tumor Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Nassrollah Jabbari
- Solid Tumor Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Roholah Sharifi
- Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - Mahdi Ahmadi
- Tuberculosis and lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Vahhabi
- Department of Immunology and Genetics, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Seyyed Javad Seyedzadeh
- Department of Medical Entomology and Vector Control, School of Public Health, Urmia University of Medical Sciences, Urmia, Iran; Social Determinants of Health Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Muhammad Nawaz
- Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Sławomir Szafert
- Faculty of Chemistry, University of Wrocław, F. Joliot Curie 14, 50383 Wrocław, Poland
| | - Monireh Mahmoodi
- Department of biology, Faculty of Science, Arak University, Arak, Iran
| | - Esmaiel Jabbari
- Department of Chemical Engineering, University of South Carolina, Columbia, SC, United States
| | - Rahim Asghari
- Department of Oncology, Imam Khomeini hospital, Urmia University of Medical Sciences, Urmia, Iran
| | - Jafar Rezaie
- Solid Tumor Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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24
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Current Advances in Red Blood Cell Generation Using Stem Cells from Diverse Sources. Stem Cells Int 2019; 2019:9281329. [PMID: 31467565 PMCID: PMC6701316 DOI: 10.1155/2019/9281329] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 06/02/2019] [Accepted: 07/01/2019] [Indexed: 12/29/2022] Open
Abstract
Blood transfusions hold an indispensable part in the modern healthcare system. Up to date, the blood supply is largely dependent on donations. Unfortunately, collecting the clinical-grade blood products has become a challenging mission due to accelerated population aging, which not only increases the need for blood transfusions but also decreases the number of healthy donors. Moreover, individuals with severe hematological abnormalities or rare blood phenotypes need alternative therapeutic approaches instead of conventional blood transfusion. In these aspects, the concept of in vitro/ex vivo production of blood cells has been emerging and many attempts have been focused on manufacturing mature erythrocytes, so-called red blood cells (RBCs), the most common and important component among the blood derivatives. In this review, we provide a general overview regarding the current strategies for generating RBCs from various stem cell sources including pluripotent stem cells (PSCs) as well as circulating blood stem cells and the remaining challenges that must be overcome prior to their practical application.
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25
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Lu X, Lodi A, Konopleva M, Tiziani S. Three-Dimensional Leukemia Co-Culture System for In Vitro High-Content Metabolomics Screening. SLAS DISCOVERY 2019; 24:817-828. [PMID: 31345091 DOI: 10.1177/2472555219860446] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Metabolomics is increasingly applied to investigate different individuals and time-dependent responses to environmental stimuli. Rapid data acquisition and improved detection limits of direct infusion mass spectrometry (DIMS) are paving the way for applications of metabolomics in preclinical screening, opening new opportunities in drug discovery and personalized medicine. Three-dimensional (3D) cell culture systems, which mimic the in vivo cell microenvironment, are well recognized as tissue and organ substitutes. Here, we investigated cell viability and induction of reactive oxygen species (ROS) in stromal cells cultured in various 3D systems as well as the standard monolayer culture to evaluate which system provides the most favorable growing conditions. The selected 3D system was then tested for use in 3D co-culture of leukemia and stromal cells for DIMS-based high-throughput/high-content metabolic drug screens. The NanobioMatrix-poly(ε-caprolactone) (NBM-PCL) scaffold resulted in the lowest ROS production, supported rapid cell proliferation, and was suitable for the 96- and 384-well plate formats. Doxorubicin treatment in leukemia co-cultured with stromal cells induced some unique metabolic responses that drastically differed from those observed in leukemia cells alone. The DIMS results also showed that the drug-induced metabolic modulations in both normal and cancer cells were weakened by co-culturing even at high treatment doses, thereby demonstrating the value of the 3D co-culture high-content metabolic drug screen. In conclusion, we optimized a high sample throughput method for 3D co-culture with a DIMS-based high-content metabolic drug screen and drug development.
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Affiliation(s)
- Xiyuan Lu
- 1 Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA.,2 Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
| | - Alessia Lodi
- 1 Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA.,2 Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
| | - Marina Konopleva
- 3 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Stefano Tiziani
- 1 Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX, USA.,2 Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
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26
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Kim JE, Lee EJ, Wu Y, Kang YG, Shin JW. The combined effects of hierarchical scaffolds and mechanical stimuli on ex vivo expansion of haematopoietic stem/progenitor cells. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2019; 47:586-593. [PMID: 30831031 DOI: 10.1080/21691401.2019.1573180] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
We describe the ex vivo expansion of haematopoietic stem/progenitor cells (HSPCs) with consideration of their eventual in-vivo niche. We firstly fabricated hierarchically structured scaffolds (lattices derived via three-dimensional plotting combined with electrospun submicron fibers coated with vitronectin to increase cell affinity). We also applied intermittent hydrostatic pressure (IHP) to mimic the physical environment of the in vivo niche. In the absence of mechanical stimuli, the cell phenotype (CD34+, CD34+CD38-) remained excellent in the vitronectin-treated group. Two IHP regimens were tested; optimally, cells were pressurized (20 kPa) for 2 min and then rested for 13 min. On day 7 of culture, the total cell number had increased 21.2-fold and that of CD34+ cells 10.94-fold. CD34+ and CD34+CD38- cells constituted 44.50 and 44.07% of total cells, respectively. Colony-forming counts and the long-term culture-initiating cell assay showed that clonogenic potential was greatly improved under our experimental conditions. Scaffolds with hierarchical structures were valuable in this context. Furthermore, ex vivo expansion of HSPCs was improved by physical stimulation.
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Affiliation(s)
- Ji Eun Kim
- a Department of Biomedical Engineering , Inje University , Gimhae , Gyeongsangnam-do , Republic of Korea
| | - Eun Jin Lee
- a Department of Biomedical Engineering , Inje University , Gimhae , Gyeongsangnam-do , Republic of Korea
| | - Yanru Wu
- b Department of Health Science and Technology , Inje University , Gimhae , Gyeongsangnam-do , Republic of Korea
| | - Yun Gyeong Kang
- a Department of Biomedical Engineering , Inje University , Gimhae , Gyeongsangnam-do , Republic of Korea
| | - Jung-Woog Shin
- a Department of Biomedical Engineering , Inje University , Gimhae , Gyeongsangnam-do , Republic of Korea.,c Cardiovascular and Metabolic Disease Center/Institute of Aged Life Redesign/UHARC , Inje University , Gimhae , Republic of Korea
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27
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Braham MVJ, Li Yim ASP, Garcia Mateos J, Minnema MC, Dhert WJA, Öner FC, Robin C, Alblas J. A Human Hematopoietic Niche Model Supporting Hematopoietic Stem and Progenitor Cells In Vitro. Adv Healthc Mater 2019; 8:e1801444. [PMID: 30941927 DOI: 10.1002/adhm.201801444] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 03/05/2019] [Indexed: 12/23/2022]
Abstract
Niches in the bone marrow regulate hematopoietic stem and progenitor cell (HSPC) fate and behavior through cell-cell interactions and soluble factor secretion. The niche-HSPC crosstalk is a very complex process not completely elucidated yet. To aid further investigation of this crosstalk, a functional in vitro 3D model that closely represents the main supportive compartments of the bone marrow is developed. Different combinations of human stromal cells and hydrogels are tested for their potential to maintain CD34+ HSPCs. Cell viability, clonogenic hematopoietic potential, and surface marker expression are assessed over time. Optimal HSPC support is obtained in presence of adipogenic and osteogenic cells, together with progenitor derived endothelial cells. When cultured in a bioactive hydrogel, the supportive cells self-assemble into a hypoxic stromal network, stimulating CD34+ CD38+ cell formation, while maintaining the pool of CD34+ 38- HSPCs. HSPC clusters colocalize with the stromal networks, in close proximity to sinusoidal clusters of CD31+ endothelial cells. Importantly, the primary in vitro niche model supports HSPCs with no cytokine addition. Overall, the engineered primary 3D bone marrow environment provides an easy and reliable model to further investigate interactions between HSPCs and their endosteal and perivascular niches, in the context of normal hematopoiesis or blood-related diseases.
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Affiliation(s)
- Maaike V. J. Braham
- Department of OrthopaedicsUniversity Medical Center Utrecht Heidelberglaan 100 3584 CX Utrecht The Netherlands
- Regenerative Medicine CenterUniversity Medical Center Utrecht Uppsalalaan 8 3584 CT Utrecht The Netherlands
| | - Amélie S. P. Li Yim
- Department of OrthopaedicsUniversity Medical Center Utrecht Heidelberglaan 100 3584 CX Utrecht The Netherlands
- Regenerative Medicine CenterUniversity Medical Center Utrecht Uppsalalaan 8 3584 CT Utrecht The Netherlands
| | - Jara Garcia Mateos
- Department of OrthopaedicsUniversity Medical Center Utrecht Heidelberglaan 100 3584 CX Utrecht The Netherlands
- Regenerative Medicine CenterUniversity Medical Center Utrecht Uppsalalaan 8 3584 CT Utrecht The Netherlands
| | - Monique C. Minnema
- Department of HematologyUniversity Medical Center Utrecht Cancer Center Heidelberglaan 100 3584 CX Utrecht The Netherlands
| | - Wouter J. A. Dhert
- Faculty of Veterinary MedicineUtrecht University Yalelaan 7 3584 CL Utrecht The Netherlands
| | - F. Cumhur Öner
- Department of OrthopaedicsUniversity Medical Center Utrecht Heidelberglaan 100 3584 CX Utrecht The Netherlands
| | - Catherine Robin
- Regenerative Medicine CenterUniversity Medical Center Utrecht Uppsalalaan 8 3584 CT Utrecht The Netherlands
- Hubrecht Institute‐KNAWUniversity Medical Center Utrecht Uppsalalaan 8 3584 CT Utrecht The Netherlands
| | - Jacqueline Alblas
- Department of OrthopaedicsUniversity Medical Center Utrecht Heidelberglaan 100 3584 CX Utrecht The Netherlands
- Regenerative Medicine CenterUniversity Medical Center Utrecht Uppsalalaan 8 3584 CT Utrecht The Netherlands
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28
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Li D, Chiu G, Lipe B, Hopkins RA, Lillis J, Ashton JM, Paul S, Aljitawi OS. Decellularized Wharton jelly matrix: a biomimetic scaffold for ex vivo hematopoietic stem cell culture. Blood Adv 2019; 3:1011-1026. [PMID: 30940636 PMCID: PMC6457237 DOI: 10.1182/bloodadvances.2018019315] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 02/10/2019] [Indexed: 12/13/2022] Open
Abstract
Hematopoietic stem progenitor cells (HSPCs) reside in the bone marrow (BM) hematopoietic "niche," a special 3-dimensional (3D) microenvironment that regulates HSPC self-renewal and multipotency. In this study, we evaluated a novel 3D in vitro culture system that uses components of the BM hematopoietic niche to expand umbilical cord blood (UCB) CD34+ cells. We developed this model using decellularized Wharton jelly matrix (DWJM) as an extracellular matrix (ECM) scaffold and human BM mesenchymal stromal cells (MSCs) as supporting niche cells. To assess the efficacy of this model in expanding CD34+ cells, we analyzed UCB CD34+ cells, following culture in DWJM, for proliferation, viability, self-renewal, multilineage differentiation, and transmigration capability. We found that DWJM significantly expanded UCB HSPC subset. It promoted UCB CD34+ cell quiescence, while maintaining their viability, differentiation potential with megakaryocytic differentiation bias, and clonogenic capacity. DWJM induced an increase in the frequency of c-kit+ cells, a population with enhanced self-renewal ability, and in CXCR4 expression in CD34+ cells, which enhanced their transmigration capability. The presence of BM MSCs in DWJM, however, impaired UCB CD34+ cell transmigration and suppressed CXCR4 expression. Transcriptome analysis indicated that DWJM upregulates a set of genes that are specifically involved in megakaryocytic differentiation, cell mobility, and BM homing. Collectively, our results indicate that the DWJM-based 3D culture system is a novel in vitro model that supports the proliferation of UCB CD34+ cells with enhanced transmigration potential, while maintaining their differentiation potential. Our findings shed light on the interplay between DWJM and BM MSCs in supporting the ex vivo culture of human UCB CD34+ cells for use in clinical transplantation.
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Affiliation(s)
- Dandan Li
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS
| | - Grace Chiu
- Hematology/Oncology and Bone Marrow Transplant Program, Department of Medicine, University of Rochester Medical Center, Rochester, NY
| | - Brea Lipe
- Hematology/Oncology and Bone Marrow Transplant Program, Department of Medicine, University of Rochester Medical Center, Rochester, NY
| | - Richard A Hopkins
- Cardiac Surgery Research Laboratories, Children's Mercy Hospital and Clinics, Kansas City, MO; and
| | - Jacquelyn Lillis
- Genomics Research Center, University of Rochester Medical Center, Rochester, NY
| | - John M Ashton
- Genomics Research Center, University of Rochester Medical Center, Rochester, NY
| | - Soumen Paul
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS
| | - Omar S Aljitawi
- Hematology/Oncology and Bone Marrow Transplant Program, Department of Medicine, University of Rochester Medical Center, Rochester, NY
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29
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Effect of nutritional supplement on bone marrow-derived mesenchymal stem cells from aplastic anaemia. Br J Nutr 2019; 119:748-758. [PMID: 29569543 DOI: 10.1017/s0007114518000399] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Aplastic anaemia (AA) is characterised by pancytopenia resulting from a marked reduction in haemopoietic stem cells (HSC). The regulation of haemopoiesis depends on the interaction between HSC and various cells of the bone marrow (BM) microenvironment, including BM-derived mesenchymal stromal cells (BMSC). The purpose of this study was to analyse the biological effect of nutritional supplement (NS), a dietary supplement consisting of thirty-six compounds: amino acids, nucleotides, vitamins and micronutrients on the BMSC of AA rats. The AA rat model was established by irradiating X-ray (2·5 Gy) and intraperitoneal injections of cyclophosphamide (35 mg/kg; Sigma) and chloramphenicol (35 mg/kg; Sigma). Then AA rats were fed with NS in a dose-dependent manner (2266·95, 1511·3, 1057·91 mg/kg d) by intragastric administration. The effect of NS on the BMSC of AA rats was analysed. As compared with AA rats, NS treatment significantly improved these peripheral blood parameters and stimulated the proliferation of total femoral nucleated cells. NS treatment affected proliferative behaviour of BMSC and suppressed BMSC differentiation to adipocytes. Furthermore, NS treatment of AA rats accelerated osteogenic differentiation of BMSC and enhanced bone mineral density. Co-incubation of HSC with mesenchymal stromal cells and serum from AA rats subjected to high-dose NS markedly improved the yield of CD34+cells. Protein microarray analysis revealed that there were eleven differentially expressed proteins in the NS group compared with the AA rat group. The identified specific NS might be implicated in rehabilitation of BMSC in AA rats, suggesting their potential of nutritional support in AA treatment.
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30
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Calcium phosphate scaffolds with defined interconnecting channel structure provide a mimetic 3D niche for bone marrow metastasized tumor cell growth. Acta Biomater 2019; 88:527-539. [PMID: 30797105 DOI: 10.1016/j.actbio.2019.02.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 01/19/2019] [Accepted: 02/19/2019] [Indexed: 01/17/2023]
Abstract
Metastasis of tumor cells in the bone marrow (BM) is a multi-step and highly dynamic process during which cells succumb important phenotypic changes. Behavior of disseminated tumor cells in BM is strictly regulated by three-dimensional (3D) cell-cell and cell-matrix interactions. In this study, we explored whether the β-tricalcium-phosphate (β-TCP) scaffolds with a tailored interconnecting channel structure could enable appropriate 3D mimetic BM microenvironment for the growth of metastatic neuroblastoma cells. The scaffolds provided the mechanical support for human mesenchymal stromal cells (hMSC) allowing them to proliferate, differentiate towards osteoblasts, and produce the deposits of extracellular matrix inside the interconnected channels. The in vitro microenvironment shaped by stromal cells was then tailored by neuroblastoma tumor cells. Immunohistological analyses confirmed the organization of tumor cells into the forms of spheres only when co-cultured with hMSC-derived osteoblasts. The growing rate of tumor cells in 3D conditions was less marked comparing to the one of the cells grown as 2D monolayer as confirmed by decreased Ki-67 expression. Instead, the 3D culturing of neuroblastoma cells inside supportive stroma promoted cell quiescence as sustained by increased p27 level. A balance between cell proliferation, survival, and differentiation was more evident for tumor cells grown inside the 3D scaffolds, thus mirroring better the situation that occurs in vivo where the cells do not follow the exponential growth rate. We conclude that the proposed 3D β-TCP scaffold type provides a mimetic 3D in vitro niche suitable for studying behavior of BM metastasized tumor cells. STATEMENT OF SIGNIFICANCE: Bone marrow (BM) niche is a favorite target of metastatic neuroblastoma cells. To better address the molecular mechanisms that sustain spatiotemporal organization of neuroblastoma cells in the marrow we mimicked the three-dimensional (3D) assembly of stromal and tumor cells inside β-tricalcium-phosphate (β-TCP) scaffolds. β-TCP scaffolds with a tailored interconnecting channel structure provided mechanical support to mesenchymal stromal cells allowing them to differentiate towards osteoblasts and to produce extracellular matrix. A dynamic cell-matrix interplay favored the characteristic rosette-like growth of metastatic neuroblastoma cells and triggered their quiescence. With our study, we confirmed the potential of β-TCP scaffolds with reproduced BM niche as a cost-effective in vitro model for the growth of disseminated tumor cells, and for related biological and pharmacological surveys.
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31
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Kim H, Bae C, Kook YM, Koh WG, Lee K, Park MH. Mesenchymal stem cell 3D encapsulation technologies for biomimetic microenvironment in tissue regeneration. Stem Cell Res Ther 2019; 10:51. [PMID: 30732645 PMCID: PMC6367797 DOI: 10.1186/s13287-018-1130-8] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cell (MSC) encapsulation technique has long been emerged in tissue engineering as it plays an important role in implantation of stem cells to regenerate a damaged tissue. MSC encapsulation provides a mimic of a three-dimensional (3D) in vivo environment to maintain cell viability and to induce the stem cell differentiation which regulates MSC fate into multi-lineages. Moreover, the 3D matrix surrounding MSCs protects them from the human innate immune system and allows the diffusion of biomolecules such as oxygen, cytokines, and growth factors. Therefore, many technologies are being developed to create MSC encapsulation platforms with diverse materials, shapes, and sizes. The conditions of the platform are determined by the targeted tissue and translation method. This review introduces several details of MSC encapsulation technologies such as micromolding, electrostatic droplet extrusion, microfluidics, and bioprinting and their application for tissue regeneration. Lastly, some of the challenges and future direction of MSC encapsulation technologies as a cell therapy-based tissue regeneration method will be discussed.
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Affiliation(s)
- Hyerim Kim
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
| | - Chaewon Bae
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
| | - Yun-Min Kook
- Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul, Republic of Korea
| | - Won-Gun Koh
- Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul, Republic of Korea
| | - Kangwon Lee
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea. .,Advanced Institutes of Convergence Technology, Suwon, Republic of Korea.
| | - Min Hee Park
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea. .,Center for Convergence Bioceramic Materials, Korea Institute of Ceramic Engineering and Technology, Cheongju, Republic of Korea.
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32
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Torisawa YS. Microfluidic Organs-on-Chips to Reconstitute Cellular Microenvironments. Bioanalysis 2019. [DOI: 10.1007/978-981-13-6229-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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33
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Bello AB, Park H, Lee SH. Current approaches in biomaterial-based hematopoietic stem cell niches. Acta Biomater 2018; 72:1-15. [PMID: 29578087 DOI: 10.1016/j.actbio.2018.03.028] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 02/07/2018] [Accepted: 03/14/2018] [Indexed: 12/20/2022]
Abstract
Hematopoietic stem cells (HSCs) are multipotent progenitor cells that can differentiate and replenish blood and immune cells. While there is a growing demand for autologous and allogeneic HSC transplantation owing to the increasing incidence of hereditary and hematologic diseases, the low population of HSCs in cord-blood and bone marrow (the main source of HSCs) hinders their medical applicability. Several cytokine and growth factor-based methods have been developed to expand the HSCs in vitro; however, the expansion rate is low, or the expanded cells fail to survive upon engraftment. This is at least in part because the overly simplistic polystyrene culture substrates fail to fully replicate the microenvironments or niches where these stem cells live. Bone marrow niches are multi-dimensional, complex systems that involve both biochemical (cells, growth factors, and cytokines) and physiochemical (stiffness, O2 concentration, and extracellular matrix presentation) factors that regulate the quiescence, proliferation, activation, and differentiation of the HSCs. Although several studies have been conducted on in vitro HSC expansion via 2D and 3D biomaterial-based platforms, additional work is required to engineer an effective biomaterial platform that mimics bone marrow niches. In this study, the factors that regulate the HSC in vivo were explained and their applications in the engineering of a bone marrow biomaterial-based platform were discussed. In addition, current approaches, challenges, and the future direction of a biomaterial-based culture and expansion of the HSC were examined. STATEMENT OF SIGNIFICANCE Hematopoietic stem cells (HSC) are multipotent cells that can differentiate and replace the blood and immune cells of the body. However, in vivo, there is a low population of these cells, and thus their use in biotherapeutic and medical applications is limited (i.e., bone marrow transplantation). In this review, the biochemical factors (growth factors, cytokines, co-existing cells, ECM, gas concentrations, and differential gene expression) that may regulate the over-all fate of HSC, in vivo, were summarized and discussed. Moreover, different conventional and recent biomaterial platforms were reviewed, and their potential in generating a biomaterial-based, BM niche-mimicking platform for the efficient growth and expansion of clinically relevant HSCs in-vitro, was discussed.
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Affiliation(s)
- Alvin Bacero Bello
- School of Integrative Engineering, Chung-Ang University, Seoul 06911, Republic of Korea; Department of Biomedical Science, CHA University, Seongnam-Si 13488, Republic of Korea
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, Seoul 06911, Republic of Korea.
| | - Soo-Hong Lee
- Department of Biomedical Science, CHA University, Seongnam-Si 13488, Republic of Korea.
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34
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Timari H, Shamsasenjan K, Movassaghpour A, Akbarzadehlaleh P, Pashoutan Sarvar D, Aqmasheh S. The Effect of Mesenchymal Stem Cell-Derived Extracellular Vesicles on Hematopoietic Stem Cells Fate. Adv Pharm Bull 2017; 7:531-546. [PMID: 29399543 PMCID: PMC5788208 DOI: 10.15171/apb.2017.065] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 11/25/2017] [Accepted: 11/28/2017] [Indexed: 12/16/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are multipotent stem cells, with self-renewal ability as well as ability to generate all blood cells. Mesenchymal stem cells (MSCs) are multipotent stem cells, with self-renewal ability, and capable of differentiating into a variety of cell types. MSCs have supporting effects on hematopoiesis; through direct intercellular communications as well as secreting cytokines, chemokines, and extracellular vesicles (EVs). Recent investigations demonstrated that some biological functions and effects of MSCs are mediated by their EVs. MSC-EVs are the cell membrane and endosomal membrane compartments, which are important mediators in the intercellular communications. MSC-EVs contain some of the molecules such as proteins, mRNA, siRNA, and miRNA from their parental cells. MSC-EVs are able to inhibit tumor, repair damaged tissue, and modulate immune system responses. MSC-EVs compared to their parental cells, may have the specific safety advantages such as the lower potential to trigger immune system responses and limited side effects. Recently some studies demonstrated the effect of MSC-EVs on the expansion, differentiation, and clinical applications of HSCs such as improvement of hematopoietic stem cell transplantation (HSCT) and inhibition of graft versus host disease (GVHD). HSCT may be the only therapeutic choice for patients who suffer from malignant and non-malignant hematological disorders. However, there are several severe side effects such GVHD that restricts the successfulness of HSCT. In this review, we will discuss the most important effects of MSCs and MSC-EVs on the improvement of HSCT, inhibition and treatment of GVHD, as well as, on the expansion of HSCs.
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Affiliation(s)
- Hamze Timari
- Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasenjan
- Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aliakbar Movassaghpour
- Hematology Oncology Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Parvin Akbarzadehlaleh
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Sara Aqmasheh
- Stem Cell Research Centre, Tabriz University of Medical Sciences, Tabriz, Iran
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35
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Costa MHG, de Soure AM, Cabral JMS, Ferreira FC, da Silva CL. Hematopoietic Niche - Exploring Biomimetic Cues to Improve the Functionality of Hematopoietic Stem/Progenitor Cells. Biotechnol J 2017; 13. [PMID: 29178199 DOI: 10.1002/biot.201700088] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 10/27/2017] [Indexed: 12/19/2022]
Abstract
The adult bone marrow (BM) niche is a complex entity where a homeostatic hematopoietic system is maintained through a dynamic crosstalk between different cellular and non-cellular players. Signaling mechanisms triggered by cell-cell, cell-extracellular matrix (ECM), cell-cytokine interactions, and local microenvironment parameters are involved in controlling quiescence, self-renewal, differentiation, and migration of hematopoietic stem/progenitor cells (HSPC). A promising strategy to more efficiently expand HSPC numbers and tune their properties ex vivo is to mimic the hematopoietic niche through integration of adjuvant stromal cells, soluble cues, and/or biomaterial-based approaches in HSPC culture systems. Particularly, mesenchymal stem/stromal cells (MSC), through their paracrine activity or direct contact with HSPC, are thought to be a relevant niche player, positioning HSPC-MSC co-culture as a valuable platform to support the ex vivo expansion of hematopoietic progenitors. To improve the clinical outcome of hematopoietic cell transplantation (HCT), namely when the available HSPC are present in a limited number such is the case of HSPC collected from umbilical cord blood (UCB), ex vivo expansion of HSPC is required without eliminating the long-term repopulating capacity of more primitive HSC. Here, we will focus on depicting the characteristics of co-culture systems, as well as other bioengineering approaches to improve the functionality of HSPC ex vivo.
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Affiliation(s)
- Marta H G Costa
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - António M de Soure
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Joaquim M S Cabral
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Frederico Castelo Ferreira
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Cláudia L da Silva
- Department of Bioengineering and iBB-Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal.,The Discoveries Centre for Regenerative and Precision Medicine, Lisbon Campus, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
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Broglie L, Margolis D, Medin JA. Yin and Yang of mesenchymal stem cells and aplastic anemia. World J Stem Cells 2017; 9:219-226. [PMID: 29321823 PMCID: PMC5746642 DOI: 10.4252/wjsc.v9.i12.219] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/14/2017] [Accepted: 10/17/2017] [Indexed: 02/07/2023] Open
Abstract
Acquired aplastic anemia (AA) is a bone marrow failure syndrome characterized by peripheral cytopenias and bone marrow hypoplasia. It is ultimately fatal without treatment, most commonly from infection or hemorrhage. Current treatments focus on suppressing immune-mediated destruction of bone marrow stem cells or replacing hematopoietic stem cells (HSCs) by transplantation. Our incomplete understanding of the pathogenesis of AA has limited development of targeted treatment options. Mesenchymal stem cells (MSCs) play a vital role in HSC proliferation; they also modulate immune responses and maintain an environment supportive of hematopoiesis. Some of the observed clinical manifestations of AA can be explained by mesenchymal dysfunction. MSC infusions have been shown to be safe and may offer new approaches for the treatment of this disorder. Indeed, infusions of MSCs may help suppress auto-reactive, T-cell mediated HSC destruction and help restore an environment that supports hematopoiesis. Small pilot studies using MSCs as monotherapy or as adjuncts to HSC transplantation have been attempted as treatments for AA. Here we review the current understanding of the pathogenesis of AA and the function of MSCs, and suggest that MSCs should be a target for further research and clinical trials in this disorder.
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Affiliation(s)
- Larisa Broglie
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, United States.
| | - David Margolis
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Jeffrey A Medin
- Departments of Pediatrics and Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States
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37
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Li Z, Niu X, Xiao S, Ma H. Retinoic acid ameliorates photoaged skin through RAR‑mediated pathway in mice. Mol Med Rep 2017; 16:6240-6247. [PMID: 28849147 DOI: 10.3892/mmr.2017.7336] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 08/14/2017] [Indexed: 11/06/2022] Open
Abstract
Retinoic acid (RA), the bioactive metabolite of vitamin A, has demonstrated efficacy in the treatment of photoaged skin; however, the mechanism of action of RA remains unclear. The aim of the present study was to examine whether the therapeutic effects of RA on photoaged skin are mediated by retinoic acid receptor (RAR) and/or retinoid X receptor (RXR) in mice, and to investigate the underlying mechanism. Photoaged skin in Imprinting Control Region mice was induced by repeated exposure to ultraviolet (UV) irradiation. Mice were randomly divided into nine groups: Normal; UV control; all‑trans retinoic acid (ATRA); ATRA + RAR antagonist; ATRA + RXR antagonist; RAR agonist; RAR agonist + RAR antagonist; RXR agonist; and RXR agonist + RXR antagonist. Masson's trichrome staining was used to examine skin collagen fibers. Hydroxyproline assays were used to determine collagen content. The protein expression of matrix metalloproteinase (MMP)‑3, MMP‑13, type I procollagen, c‑Jun and c‑Fos was detected using western blot analysis. The results demonstrated that ATRA and RAR agonist ameliorated the UV‑induced damage to skin collagen fibers, and increased the collagen content in photoaged skin through RAR. Furthermore, ATRA and RAR agonist stimulated type I procollagen protein expression, and inhibited MMP‑3, MMP‑13 and c‑Jun protein expression through RAR in photoaged skin. However, ATRA and RAR agonist exhibited no significant effect on the protein expression of c‑Fos in photoaged skin. These findings suggest that RA ameliorates photoaged skin through a RAR‑mediated signaling pathway in mice.
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Affiliation(s)
- Zhangjun Li
- Department of Dermatology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Xinwu Niu
- Department of Dermatology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Shengxiang Xiao
- Department of Dermatology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Huiqun Ma
- Department of Dermatology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
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Chen L, Ran Q, Xiang Y, Xiang L, Chen L, Li F, Wu J, Wu C, Li Z. Co-Activation of PKC-δ by CRIF1 Modulates Oxidative Stress in Bone Marrow Multipotent Mesenchymal Stromal Cells after Irradiation by Phosphorylating NRF2 Ser40. Theranostics 2017; 7:2634-2648. [PMID: 28819452 PMCID: PMC5558558 DOI: 10.7150/thno.17853] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 04/19/2017] [Indexed: 12/26/2022] Open
Abstract
The high mortality associated with pancytopenia and multi-organ failure resulting from hematopoietic disorders of acute radiation syndrome (h-ARS) creates an urgent need for developing more effective treatment strategies. Here, we showed that bone marrow multipotent mesenchymal stromal cells (BMMSCs) effectively regulate oxidative stress following radiative injury, which might be on account of irradiation-induced elevation of protein levels of CR6-interacting factor 1(CRIF1) and nuclear factor E2-related factor 2(NRF2). Crif1-knockdown BMMSCs presented increased oxidative stress and apoptosis after irradiation, which were partially due to a suppressed antioxidant response mediated by decreased NRF2 nuclear translocation. Co-immunoprecipitation (Co-IP) experiments indicated that CRIF1 interacted with protein kinase C-δ (PKC-δ). NRF2 Ser40 phosphorylation was inhibited in Crif1-deficient BMMSCs even in the presence of three kinds of PKC agonists, suggesting that CRIF1 might co-activate PKC-δ to phosphorylate NRF2 Ser40. After radiative injury, the supporting effect of BMMSCs for the colony forming ability of HSCs in vitro was reduced, and the deficiency of CRIF1 aggravated such damage. Thus, CRIF1 plays an essential role in PKC-δ/NRF2 pathway modulation to alleviate oxidative stress in BMMSCs after irradiative injury, and at some level it may maintain the HSCs-supporting effect of BMMSCs after radiative injuries.
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