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Vogt A, Faher A, Kucharczak J, Birch M, McCaskie A, Khan W. The Effects of Gender on Mesenchymal Stromal Cell (MSC) Proliferation and Differentiation In Vitro: A Systematic Review. Int J Mol Sci 2024; 25:13585. [PMID: 39769346 PMCID: PMC11677156 DOI: 10.3390/ijms252413585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/05/2024] [Accepted: 12/08/2024] [Indexed: 01/11/2025] Open
Abstract
Mesenchymal stromal cells (MSCs) have the potential for novel treatments of several musculoskeletal conditions due to their ability to differentiate into several cell lineages including chondrocytes, adipocytes and osteocytes. Researchers are exploring whether this could be utilized for novel therapies for joint afflictions. The role of gender in the ability of MSCs to differentiate and proliferate into different cells has not been clearly defined. This systematic review aims to report the current literature on studies, characterized by high quality and in-depth analysis even though quantitatively limited, that have looked at the role of gender in the differentiation and proliferation of MSCs. Sixteen studies were identified during the literature search, reporting 533 patients, of which 202 were male and 331 were female. MSC proliferation, phenotypic analysis and differentiation are reported and contrasted in terms of donor gender. Heterogeneity in methodologies across studies likely contributes to the inconclusive findings presented here, with no discernible statistical disparity observed between genders in differentiation traits. Nevertheless, the proliferation results indicate a notable gender-related impact. Future investigations should aim to ascertain the potential influence of gender on MSC proliferation capacities more conclusively, emphasizing the necessity of standardized protocols for MSC analyses to enhance accuracy and comparability across studies.
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Affiliation(s)
- Antonia Vogt
- Division of Trauma & Orthopaedic Surgery, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK; (A.V.)
| | - Anissa Faher
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 2SP, UK
| | - Joanna Kucharczak
- School of Clinical Medicine, University of Cambridge, Cambridge CB2 2SP, UK
| | - Mark Birch
- Division of Trauma & Orthopaedic Surgery, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK; (A.V.)
| | - Andrew McCaskie
- Division of Trauma & Orthopaedic Surgery, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK; (A.V.)
| | - Wasim Khan
- Division of Trauma & Orthopaedic Surgery, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK; (A.V.)
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2
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Tang X, Zhou F, Wang S, Wang G, Bai L, Su J. Bioinspired injectable hydrogels for bone regeneration. J Adv Res 2024:S2090-1232(24)00486-7. [PMID: 39505143 DOI: 10.1016/j.jare.2024.10.032] [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: 01/07/2024] [Revised: 09/28/2024] [Accepted: 10/27/2024] [Indexed: 11/08/2024] Open
Abstract
The effective regeneration of bone/cartilage defects remains a significant clinical challenge, causing irreversible damage to millions annually.Conventional therapies such as autologous or artificial bone grafting often yield unsatisfactory outcomes, emphasizing the urgent need for innovative treatment methods. Biomaterial-based strategies, including hydrogels and active scaffolds, have shown potential in promoting bone/cartilage regeneration. Among them, injectable hydrogels have garnered substantial attention in recent years on account of their minimal invasiveness, shape adaptation, and controlled spatiotemporal release. This review systematically discusses the synthesis of injectable hydrogels, bioinspired approaches-covering microenvironment, structural, compositional, and bioactive component-inspired strategies-and their applications in various bone/cartilage disease models, highlighting bone/cartilage regeneration from an innovative perspective of bioinspired design. Taken together, bioinspired injectable hydrogels offer promising and feasible solutions for promoting bone/cartilage regeneration, ultimately laying the foundations for clinical applications. Furthermore, insights into further prospective directions for AI in injectable hydrogels screening and organoid construction are provided.
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Affiliation(s)
- Xuan Tang
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China
| | - Fengjin Zhou
- Department of Orthopaedics, Honghui Hospital, Xi'an Jiao Tong University, Xi'an 710000, China
| | - Sicheng Wang
- National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China; Department of Orthopedics Trauma, Shanghai Zhongye Hospital, Shanghai 201900, China
| | - Guangchao Wang
- Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
| | - Long Bai
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China; Wenzhou Institute of Shanghai University, Wenzhou 325000, China.
| | - Jiacan Su
- Organoid Research Center, Institute of Translational Medicine, Shanghai University, Shanghai 200444, China; Department of Orthopedics, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai 200444, China.
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Xiao X, Zhang M, Qian Y, Wang X, Wu Q. KLF9 regulates osteogenic differentiation of mesenchymal stem cells. J Mol Histol 2024; 55:503-512. [PMID: 38801643 DOI: 10.1007/s10735-024-10204-6] [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: 12/31/2023] [Accepted: 05/16/2024] [Indexed: 05/29/2024]
Abstract
Osteoporosis is a progressive skeletal disease which is characterized by reduced bone mass and degradation of bone microstructure. Mesenchymal stem cells (MSCs) have the potential to inhibit osteoporosis since they are multipotent stem cells that can differentiate into multiple types of cells including osteoblasts. Hence the mechanism of osteogenic differentiation of MSCs deserves comprehensive study. Here we report that KLF9 is a novel regulator in osteogenic differentiation of MSCs. We observed that depletion of KLF9 can largely compromise the osteogenic differentiation ability of MSCs. In addition, we revealed that inhibition of the PI3K-Akt pathway could also affect osteogenic differentiation since KLF9 depletion inhibits PI3K expression. Finally, we discovered that KLF9 expression can be induced by dexamethasone which is an essential component in osteogenic induction medium. Taken together, our study provides new insights into the regulatory role of KLF9 in osteogenic differentiation of MSCs.
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Affiliation(s)
- Xiaoxiao Xiao
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
- Faculty of Chinese Medicine, Hunan Traditional Chinese Medical College, Zhuzhou, China
| | - Ming Zhang
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yiwei Qian
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Xuepeng Wang
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Qiang Wu
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
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4
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Chiu H, Chau Fang A, Chen YH, Koi RX, Yu KC, Hsieh LH, Shyu YM, Amer TA, Hsueh YJ, Tsao YT, Shen YJ, Wang YM, Chen HC, Lu YJ, Huang CC, Lu TT. Mechanistic and Kinetic Insights into Cellular Uptake of Biomimetic Dinitrosyl Iron Complexes and Intracellular Delivery of NO for Activation of Cytoprotective HO-1. JACS AU 2024; 4:1550-1569. [PMID: 38665642 PMCID: PMC11040670 DOI: 10.1021/jacsau.4c00064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 02/29/2024] [Accepted: 03/19/2024] [Indexed: 04/28/2024]
Abstract
Dinitrosyl iron unit (DNIU), [Fe(NO)2], is a natural metallocofactor for biological storage, delivery, and metabolism of nitric oxide (NO). In the attempt to gain a biomimetic insight into the natural DNIU under biological system, in this study, synthetic dinitrosyl iron complexes (DNICs) [(NO)2Fe(μ-SCH2CH2COOH)2Fe(NO)2] (DNIC-COOH) and [(NO)2Fe(μ-SCH2CH2COOCH3)2Fe(NO)2] (DNIC-COOMe) were employed to investigate the structure-reactivity relationship of mechanism and kinetics for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective heme oxygenase (HO)-1. After rapid cellular uptake of dinuclear DNIC-COOMe through a thiol-mediated pathway (tmax = 0.5 h), intracellular assembly of mononuclear DNIC [(NO)2Fe(SR)(SCys)]n-/[(NO)2Fe(SR)(SCys-protein)]n- occurred, followed by O2-induced release of free NO (tmax = 1-2 h) or direct transfer of NO to soluble guanylate cyclase, which triggered the downstream HO-1. In contrast, steady kinetics for cellular uptake of DNIC-COOH via endocytosis (tmax = 2-8 h) and for intracellular release of NO (tmax = 4-6 h) reflected on the elevated activation of cytoprotective HO-1 (∼50-150-fold change at t = 3-10 h) and on the improved survival of DNIC-COOH-primed mesenchymal stem cell (MSC)/human corneal endothelial cell (HCEC) under stressed conditions. Consequently, this study unravels the bridging thiolate ligands in dinuclear DNIC-COOH/DNIC-COOMe as a switch to control the mechanism, kinetics, and efficacy for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective HO-1, which poses an implication on enhanced survival of postengrafted MSC for advancing the MSC-based regenerative medicine.
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Affiliation(s)
- Han Chiu
- Institute
of Biomedical Engineering, National Tsing
Hua University, Hsinchu 30013 Taiwan
| | - Anyelina Chau Fang
- Institute
of Biomedical Engineering, National Tsing
Hua University, Hsinchu 30013 Taiwan
| | - Yi-Hong Chen
- Institute
of Biomedical Engineering, National Tsing
Hua University, Hsinchu 30013 Taiwan
| | - Ru Xin Koi
- Institute
of Biomedical Engineering, National Tsing
Hua University, Hsinchu 30013 Taiwan
| | - Kai-Ching Yu
- Institute
of Biomedical Engineering, National Tsing
Hua University, Hsinchu 30013 Taiwan
| | - Li-Hung Hsieh
- Institute
of Biomedical Engineering, National Tsing
Hua University, Hsinchu 30013 Taiwan
| | - Yueh-Ming Shyu
- Institute
of Biomedical Engineering, National Tsing
Hua University, Hsinchu 30013 Taiwan
| | - Tarik Abdelkareem
Mostafa Amer
- Department
of Biological Science and Technology, Institute of Molecular Medicine
and Bioengineering, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Yi-Jen Hsueh
- Department
of Ophthalmology and Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Yu-Ting Tsao
- Department
of Ophthalmology and Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Yang-Jin Shen
- College
of Medicine, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan
- Department
of Neurosurgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Yun-Ming Wang
- Department
of Biological Science and Technology, Institute of Molecular Medicine
and Bioengineering, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 300, Taiwan
| | - Hung-Chi Chen
- Department
of Ophthalmology and Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- College
of Medicine, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan
| | - Yu-Jen Lu
- College
of Medicine, Chang Gung University, Kwei-San, Taoyuan 33302, Taiwan
- Department
of Neurosurgery, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Chieh-Cheng Huang
- Institute
of Biomedical Engineering, National Tsing
Hua University, Hsinchu 30013 Taiwan
| | - Tsai-Te Lu
- Institute
of Biomedical Engineering, National Tsing
Hua University, Hsinchu 30013 Taiwan
- Department
of Chemistry, National Tsing Hua University, Hsinchu 30013 Taiwan
- Department
of Chemistry, Chung Yuan Christian University, Taoyuan 32023, Taiwan
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Marrero - Berrios I, Salter SE, Hirday R, Rabolli CP, Tan A, Hung CT, Schloss RS, Yarmush ML. In vitro inflammatory multi-cellular model of osteoarthritis. OSTEOARTHRITIS AND CARTILAGE OPEN 2024; 6:100432. [PMID: 38288345 PMCID: PMC10823137 DOI: 10.1016/j.ocarto.2023.100432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 12/26/2023] [Indexed: 01/31/2024] Open
Abstract
Objective Osteoarthritis (OA) is a chronic joint disease, with limited treatment options, characterized by inflammation and matrix degradation, and resulting in severe pain or disability. Progressive inflammatory interaction among key cell types, including chondrocytes and macrophages, leads to a cascade of intra- and inter-cellular events which culminate in OA induction. In order to investigate these interactions, we developed a multi-cellular in vitro OA model, to characterize OA progression, and identify and evaluate potential OA therapeutics in response to mediators representing graded levels of inflammatory severity. Methods We compared macrophages, chondrocytes and their co-culture responses to "low" Interleukin-1 (IL-1) or "high" IL-1/tumor necrosis factor (IL-1/TNF) levels of inflammation. We also investigated response changes following the administration of dexamethasone (DEX) or mesenchymal stromal cell (MSC) treatment via a combination of gene expression and secretory changes, reflecting not only inflammation, but also chondrocyte function. Results Inflamed chondrocytes presented an osteoarthritic-like phenotype characterized by high gene expression of pro-inflammatory cytokines and chemokines, up-regulation of ECM degrading proteases, and down-regulation of chondrogenic genes. Our results indicate that while MSC treatment attenuates macrophage inflammation directly, it does not reduce chondrocyte inflammatory responses, unless macrophages are present as well. DEX however, can directly attenuate chondrocyte inflammation. Conclusions Our results highlight the importance of considering multi-cellular interactions when studying complex systems such as the articular joint. In addition, our approach, using a panel of both inflammatory and chondrocyte functional genes, provides a more comprehensive approach to investigate disease biomarkers, and responses to treatment.
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Affiliation(s)
| | - S. Elina Salter
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - Rishabh Hirday
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - Charles P. Rabolli
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - Andrea Tan
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Clark T. Hung
- Department of Biomedical Engineering, Columbia University, New York, NY, USA
| | - Rene S. Schloss
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
| | - Martin L. Yarmush
- Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA
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Pirsadeghi A, Namakkoobi N, Behzadi MS, Pourzinolabedin H, Askari F, Shahabinejad E, Ghorbani S, Asadi F, Hosseini-Chegeni A, Yousefi-Ahmadipour A, Kamrani MH. Therapeutic approaches of cell therapy based on stem cells and terminally differentiated cells: Potential and effectiveness. Cells Dev 2024; 177:203904. [PMID: 38316293 DOI: 10.1016/j.cdev.2024.203904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 11/24/2023] [Accepted: 01/30/2024] [Indexed: 02/07/2024]
Abstract
Cell-based therapy, as a promising regenerative medicine approach, has been a promising and effective strategy to treat or even cure various kinds of diseases and conditions. Generally, two types of cells are used in cell therapy, the first is the stem cell, and the other is a fully differentiated cell. Initially, all cells in the body are derived from stem cells. Based on the capacity, potency and differentiation potential of stem cells, there are four types: totipotent (produces all somatic cells plus perinatal tissues), pluripotent (produces all somatic cells), multipotent (produces many types of cells), and unipotent (produces a particular type of cells). All non-totipotent stem cells can be used for cell therapy, depending on their potency and/or disease state/conditions. Adult fully differentiated cell is another cell type for cell therapy that is isolated from adult tissues or obtained following the differentiation of stem cells. The cells can then be transplanted back into the patient to replace damaged or malfunctioning cells, promote tissue repair, or enhance the targeted organ's overall function. With increasing science and knowledge in biology and medicine, different types of techniques have been developed to obtain efficient cells to use for therapeutic approaches. In this study, the potential and opportunity of use of all cell types, both stem cells and fully differentiated cells, are reviewed.
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Affiliation(s)
- Ali Pirsadeghi
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Negar Namakkoobi
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mahtab Sharifzadeh Behzadi
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hanieh Pourzinolabedin
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Askari
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; USERN Office, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Erfan Shahabinejad
- Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; USERN Office, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Somayeh Ghorbani
- Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Asadi
- Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Ali Hosseini-Chegeni
- Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Aliakbar Yousefi-Ahmadipour
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Department of Laboratory Sciences, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Student Research Committee, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Molecular Medicine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran; Cancer and Stem Cell Research Laboratory, Faculty of Paramedicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
| | - Mohammad Hossein Kamrani
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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7
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Giannasi C, Della Morte E, Cadelano F, Valenza A, Casati S, Dei Cas M, Niada S, Brini AT. Boosting the therapeutic potential of cell secretome against osteoarthritis: Comparison of cytokine-based priming strategies. Biomed Pharmacother 2024; 170:115970. [PMID: 38042116 DOI: 10.1016/j.biopha.2023.115970] [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: 08/08/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 12/04/2023] Open
Abstract
The secretome, or conditioned medium (CM), from Mesenchymal Stem/stromal Cells (MSCs) has recently emerged as a promising cell-free therapeutic against osteoarthritis (OA), capable of promoting cartilage regeneration and immunoregulation. Priming MSCs with 10 ng/ml tumor necrosis factor α (TNFα) and/or 10 ng/ml interleukin 1β (IL-1β) aims at mimicking the pathological milieu of OA joints in order to target their secretion towards a pathology-tailored phenotype. Here we compare the composition of the CM obtained after 24 or 72 h from untreated and cytokine-treated adipose-derived MSCs (ASCs). The 72-hour double-primed CM presents a higher total protein yield, a larger number of extracellular vesicles, and a greater concentration of bioactive lipids, in particular sphingolipids, fatty acids, and eicosanoids. Moreover, the levels of several factors involved in immunomodulation and regeneration, such as TGF-β1, PGE2, and CCL-2, are strongly upregulated. Additionally, the differential profiling of 80 bioactive molecules indicates that primed CM is enriched in immune cell chemotaxis and migration factors. Our results indicate that pre-conditioning ASCs with inflammatory cytokines can modulate the composition of their CM, promoting the release of factors with recognized anti-inflammatory, chondroprotective, and immunoregulatory properties.
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Affiliation(s)
- Chiara Giannasi
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy; IRCCS Istituto Ortopedico Galeazzi, Milan, Italy.
| | | | - Francesca Cadelano
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy; IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
| | | | - Sara Casati
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy
| | - Michele Dei Cas
- Department of Health Sciences, University of Milan, Milan, Italy
| | | | - Anna Teresa Brini
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy; IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
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8
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Wang Z, Liao Y, Wang C, Tang C, Fang C, Luo J, Liu H, Mo X, Wang Z, Shen L, Wang J, Chen X, Yin Z, Li J, Shen W. Stem cell-based therapeutic strategies for rotator cuff tendinopathy. J Orthop Translat 2023; 42:73-81. [PMID: 37664079 PMCID: PMC10470406 DOI: 10.1016/j.jot.2023.07.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/20/2023] [Indexed: 09/05/2023] Open
Abstract
Rotator cuff tendinopathy is a common musculoskeletal disorder that imposes significant health and economic burden. Stem cell therapy has brought hope for tendon healing in patients with final stage rotator cuff tendinopathy. Some clinical trials have confirmed the effectiveness of stem cell therapy for rotator cuff tendinopathy, but its application has not been promoted and approved. There are still many issues that should be solved prior to using stem cell therapy in clinical applications. The optimal source and dose of stem cells for rotator cuff tendinopathy should be determined. We also proposed novel prospective approaches that can overcome cell population heterogeneity and standardize patient types for stem cell applications. The translational potential of this article This review explores the optimal sources of stem cells for rotator cuff tendinopathy and the principles for selecting stem cell dosages. Key strategies are provided for stem cell population standardization and recipient selection.
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Affiliation(s)
- Zetao Wang
- Department of Orthopedics, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China
- Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Orthopaedics Research Institute of Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Youguo Liao
- Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Orthopaedics Research Institute of Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Canlong Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Orthopaedics Research Institute of Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Chenqi Tang
- Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Orthopaedics Research Institute of Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Binjiang Institute of Zhejiang University, Hangzhou, China
| | - Cailian Fang
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Orthopaedics Research Institute of Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Junchao Luo
- Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Orthopaedics Research Institute of Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Hengzhi Liu
- Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Orthopaedics Research Institute of Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xianan Mo
- Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
| | - Zicheng Wang
- Department of Orthopedics, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China
| | - Lingfang Shen
- Air Force Health Care Center for Special Services, Hangzhou, China
| | | | - Xiao Chen
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Orthopaedics Research Institute of Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Zi Yin
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Orthopaedics Research Institute of Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianyou Li
- Department of Orthopedics, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China
| | - Weiliang Shen
- Department of Orthopedics, Huzhou Central Hospital, Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou, China
- Department of Orthopedic Surgery, The Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, China
- Institute of Sports Medicine, Zhejiang University, Hangzhou, China
- Orthopaedics Research Institute of Zhejiang University, Hangzhou, China
- China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China
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9
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Park D, Choi YH, Kang SH, Koh HS, In Y. Bone Marrow Aspirate Concentrate versus Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells for Combined Cartilage Regeneration Procedure in Patients Undergoing High Tibial Osteotomy: A Systematic Review and Meta-Analysis. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:634. [PMID: 36984635 PMCID: PMC10059261 DOI: 10.3390/medicina59030634] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 02/20/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023]
Abstract
Background and objectives: Cartilage regeneration using mesenchymal stem cells (MSCs) has been attempted to improve articular cartilage regeneration in varus knee osteoarthritis (OA) patients undergoing high tibial osteotomy (HTO). Bone marrow aspirate concentrate (BMAC) and human umbilical cord blood-derived MSCs (hUCB-MSCs) have been reported to be effective. However, whether BMAC is superior to hUCB-MSCs remains unclear. This systematic review and meta-analysis aimed to determine the clinical efficacy of cartilage repair procedures with BMAC or hUCB-MSCs in patients undergoing HTO. Materials and Methods: A systematic search was conducted using three global databases, PubMed, EMBASE, and the Cochrane Library, for studies in which the clinical outcomes after BMAC or hUCB-MSCs were used in patients undergoing HTO for varus knee OA. Data extraction, quality control, and meta-analysis were performed. To compare the clinical efficacy of BMAC and hUCB-MSCs, reported clinical outcome assessments and second-look arthroscopic findings were analyzed using standardized mean differences (SMDs) with 95% confidence intervals (CIs). Results: The present review included seven studies of 499 patients who received either BMAC (BMAC group, n = 169) or hUCB-MSCs (hUCB-MSC group, n = 330). Improved clinical outcomes were found in both BMAC and hUCB-MSC groups; however, a significant difference was not observed between procedures (International Knee Documentation Committee score; p = 0.91, Western Ontario and McMaster Universities OA Index; p = 0.05, Knee Society Score (KSS) Pain; p = 0.85, KSS Function; p = 0.37). On second-look arthroscopy, the hUCB-MSC group showed better International Cartilage Repair Society Cartilage Repair Assessment grade compared with the BMAC group (p < 0.001). Conclusions: Both BMAC and hUCB-MSCs with HTO improved clinical outcomes in varus knee OA patients, and there was no difference in clinical outcomes between them. However, hUCB-MSCs were more effective in articular cartilage regeneration than BMAC augmentation.
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Affiliation(s)
- Dojoon Park
- Department of Orthopedic Surgery, St. Vincent Hospital, College of Medicine, 93, Jungbu-daero, Paldal-gu, Suwon-si 16247, Republic of Korea
| | - Youn Ho Choi
- Department of Orthopedic Surgery, St. Vincent Hospital, College of Medicine, 93, Jungbu-daero, Paldal-gu, Suwon-si 16247, Republic of Korea
| | - Se Hyun Kang
- Department of Orthopedic Surgery, St. Vincent Hospital, College of Medicine, 93, Jungbu-daero, Paldal-gu, Suwon-si 16247, Republic of Korea
| | - Hae Seok Koh
- Department of Orthopedic Surgery, St. Vincent Hospital, College of Medicine, 93, Jungbu-daero, Paldal-gu, Suwon-si 16247, Republic of Korea
| | - Yong In
- Department of Orthopaedic Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
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10
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Wang F, Cheung CW, Wong SSC. Regenerative medicine for the treatment of chronic low back pain: a narrative review. J Int Med Res 2023; 51:3000605231155777. [PMID: 36802994 PMCID: PMC9941606 DOI: 10.1177/03000605231155777] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023] Open
Abstract
Low back pain (LBP) is a common and important clinical problem. In addition to pain, patients are also affected by personal, social, and economic burdens. Intervertebral disc (IVD) degeneration is a common cause of LBP, further increasing the patient's morbidity and medical costs. The limitations of current treatment strategies for long-term pain relief mean that increasing attention has been paid to regenerative medicine. We carried out a narrative review to explore the roles of four types of regenerative medicine for treating LBP: marrow-derived stem cells, growth factors, platelet-rich plasma, and prolotherapy. Marrow-derived stem cells are regarded as an ideal cell source for IVD regeneration. Growth factors may stimulate the synthesis of extracellular matrix and attenuate or reverse the degenerative process in IVD, while platelet-rich plasma, which contains multiple growth factors, is thought to be a promising alternative therapy for IVD degeneration. Prolotherapy can initiate the body's inflammatory healing response to repair injured joints and connective tissues. This review summarizes the mechanisms, in vitro and in vivo studies, and clinical applications of these four types of regenerative medicine in patients with LBP.
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Affiliation(s)
| | | | - Stanley Sau Ching Wong
- Stanley Sau Ching Wong, Room 424, Block K, Queen Mary Hospital, 102 Pok Fu Lam Road, Hong Kong 852, China.
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11
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Garay RP. Recent clinical trials with stem cells to slow or reverse normal aging processes. FRONTIERS IN AGING 2023; 4:1148926. [PMID: 37090485 PMCID: PMC10116573 DOI: 10.3389/fragi.2023.1148926] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/24/2023] [Indexed: 04/25/2023]
Abstract
Aging is associated with a decline in the regenerative potential of stem cells. In recent years, several clinical trials have been launched in order to evaluate the efficacy of mesenchymal stem cell interventions to slow or reverse normal aging processes (aging conditions). Information concerning those clinical trials was extracted from national and international databases (United States, EU, China, Japan, and World Health Organization). Mesenchymal stem cell preparations were in development for two main aging conditions: physical frailty and facial skin aging. With regard to physical frailty, positive results have been obtained in phase II studies with intravenous Lomecel-B (an allogeneic bone marrow stem cell preparation), and a phase I/II study with an allogeneic preparation of umbilical cord-derived stem cells was recently completed. With regard to facial skin aging, positive results have been obtained with an autologous preparation of adipose-derived stem cells. A further sixteen clinical trials for physical frailty and facial skin aging are currently underway. Reducing physical frailty with intravenous mesenchymal stem cell administration can increase healthy life expectancy and decrease costs to the public health system. However, intravenous administration runs the risk of entrapment of the stem cells in the lungs (and could raise safety concerns). In addition to aesthetic purposes, clinical research on facial skin aging allows direct evaluation of tissue regeneration using sophisticated and precise methods. Therefore, research on both conditions is complementary, which facilitates a global vision.
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Affiliation(s)
- Ricardo P. Garay
- Pharmacology and Therapeutics, Craven, 91360 Villemoisson-sur-Orge, France
- CNRS, National Centre of Scientific Research, Paris, France
- *Correspondence: Ricardo P. Garay,
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12
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Mizuno M, Ozeki N, Sekiya I. Safety of using cultured cells with trisomy 7 in cell therapy for treating osteoarthritis. Regen Ther 2022; 21:81-86. [PMID: 35785042 PMCID: PMC9234008 DOI: 10.1016/j.reth.2022.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/25/2022] [Accepted: 06/01/2022] [Indexed: 12/27/2022] Open
Abstract
Cell therapy is a promising alternative treatment approach currently under study for osteoarthritis (OA), the most common chronic musculoskeletal disease. However, the mesenchymal stem cells (MSCs) used in cell therapy to treat OA are usually expanded in vitro to obtain sufficient numbers for transplantation, and their safety has not been fully assessed from multiple perspectives. Analysis of karyotypic abnormalities, in particular, is important to ensure the safety of cells; however, chromosomal mutations may also occur during the cell-expansion process. In addition, there have been many reports showing chromosome abnormalities, mainly trisomy 7, in the cartilage and synovium of patients with OA as well as in normal tissues. The suitability of cells with these karyotypic abnormalities as cells for cell therapy has not been evaluated. Recently, we assessed the safety of using cells with trisomy 7 from the osteoarthritic joint of a patient for transplantation, and we followed up with the patient for 5 years. This study showed analysis for copy number variant and whole-genome sequencing, compared with blood DNA from the same patient. We did not find any abnormalities in the genes regardless of trisomy 7. No side effects were observed for at least 5 years in the human clinical study. This suggests that the transplantation of cultured cells with trisomy 7 isolated from an osteoarthritic joint and transplanted into the osteoarthritic joints of the same person is not expected to cause serious adverse events. However, it is unclear what problems may arise in the case of allogeneic transplantation. Different types of risks will also exist depending on other transplantation routes, such as localization to the knee-joint only or circulation inflow and lung entrapment. In addition, since the cause of trisomy 7 occurrence remains unclear, it is necessary to clarify the mechanism of trisomy 7 in OA to perform cell therapy for OA patients in a safe manner.
Trisomy 7 is frequently observed in the cartilage and synovium of patients with OA. MSCs with trisomy 7 did not form tumor after transplantation into mice. No side effects were observed 5 years after transplantation of MSCs with trisomy 7.
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Affiliation(s)
- Mitsuru Mizuno
- Corresponding author. Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University,1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. Fax: +81 3 5803-0192.
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13
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Dwivedi R, Yadav PK, Pandey R, Mehrotra D. Auricular reconstruction via 3D bioprinting strategies: An update. J Oral Biol Craniofac Res 2022; 12:580-588. [PMID: 35968037 DOI: 10.1016/j.jobcr.2022.07.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 07/22/2022] [Accepted: 07/28/2022] [Indexed: 10/16/2022] Open
Abstract
Image 1.
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Affiliation(s)
- Ruby Dwivedi
- King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Pradeep Kumar Yadav
- Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Rahul Pandey
- King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Divya Mehrotra
- Department of Oral and Maxillofacial Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India
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14
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Lenna S, Brozovich A, Hirase T, Paradiso F, Weiner BK, Taraballi F. Comparison between Cancellous Trabecular and Cortical Specimens from Human Lumbar Spine Samples as an Alternative Source of Mesenchymal Stromal Cells. Stem Cells Dev 2022; 31:672-683. [PMID: 36039931 DOI: 10.1089/scd.2022.0157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Due to their immunosuppressive potential and ability to differentiate into multiple musculoskeletal cell lineages, mesenchymal stromal cells (MSCs) became popular in clinical trials for the treatment of musculoskeletal disorders. The aim of this study was to isolate and characterize native populations of MSCs from human cortical and cancellous bone from the posterior elements of the lumbar spine and determine what source of MSCs yield better quality and quantity of cells to be potentially use for spinal fusion repair. We were able to show that MSCs from trabecular and cortical spine had the typical MSC morphology and expression markers; the ability to differentiate in adipocyte, chondrocyte, or osteoblast but they did not have a consistent pattern in the expression of the specific differentiation lineage genes. Moreover, MSCs from both sites demonstrated an immune suppression profile suggesting that these cells may have a more promising success in applications related to immunomodulation more than exploring their ability to drive osteogenesis to prevent nonunion in spine fusion procedures.
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Affiliation(s)
- Stefania Lenna
- Houston Methodist Research Institute, Houston, Texas, United States;
| | - Ava Brozovich
- Houston Methodist Academic Institute, Houston, Texas, United States;
| | - Takashi Hirase
- Houston Methodist Orthopedics & Sports Medicine Texas Medical Center, Houston, Texas, United States;
| | | | - Bradley K Weiner
- The Houston Methodist Research Institute, Department of Nanomedicine, Houston, Texas, United States.,Houston Methodist Hospital, Department of Orthopedic Surgery, Houston, Texas, United States;
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15
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Bowers K, Amelse L, Bow A, Newby S, MacDonald A, Sun X, Anderson D, Dhar M. Mesenchymal Stem Cell Use in Acute Tendon Injury: In Vitro Tenogenic Potential vs. In Vivo Dose Response. BIOENGINEERING (BASEL, SWITZERLAND) 2022; 9:bioengineering9080407. [PMID: 36004932 PMCID: PMC9404841 DOI: 10.3390/bioengineering9080407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 08/18/2022] [Indexed: 11/19/2022]
Abstract
Stem cell therapy for the treatment of tendon injury is an emerging clinical practice in the fields of human and veterinary sports medicine; however, the therapeutic benefit of intralesional transplantation of mesenchymal stem cells in tendonitis cases is not well designed. Questions persist regarding the overall tenogenic potential and efficacy of this treatment alone. In this study, we aimed to isolate a rat mesenchymal stem cell lineage for in vitro and in vivo use, to assess the effects of growth factor exposure in vitro on cell morphology, behavior, and tendon-associated glycoprotein production, and to assess the therapeutic potential of intralesional stem cells, as a function of dose, in vivo. First, rat adipose-derived (rAdMSC) and bone marrow-derived (rBMSC) stem cell lineages were isolated, characterized with flow cytometric analysis, and compared in terms of proliferation (MTS assay) and cellular viability (calcein AM staining). Rat AdMSCs displayed superior proliferation and more homogenous CD 73, CD 44H, and CD 90 expression as compared to rBMSC. Next, the tenogenic differentiation potential of the rAdMSC lineage was tested in vitro through isolated and combined stimulation with reported tenogenic growth factors, transforming growth factor (TGF)-β3 and connective tissue growth factor (CTGF). We found that the most effective tenogenic factor in terms of cellular morphologic change, cell alignment/orientation, sustained cellular viability, and tendon-associated glycoprotein upregulation was TGFβ3, and we confirmed that rAdMSC could be induced toward a tenogenic lineage in vitro. Finally, the therapeutic potential of rAdMSCs as a function of dose was assessed using a rat acute Achilles tendon injury model. Amounts of 5 × 105 (low dose) and 4 × 106 (high dose) were used. Subjectively, on the gross morphology, the rAdMSC-treated tendons exhibited fewer adhesions and less scar tissue than the control tendons; however, regardless of the rAdMSC dose, no significant differences in histological grade or tissue collagen I deposition were noted between the rAdMSC-treated and control tendons. Collectively, rAdMSCs exhibited appropriate stem cell markers and tenogenic potential in vitro, but the clinical efficacy of intralesional implantation of undifferentiated cells in acute tendonitis cases could not be proven. Further investigation into complementary therapeutics or specialized culture conditions prior to implantation are warranted.
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Affiliation(s)
- Kristin Bowers
- Large Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Knoxville, TN 37996-4550, USA
- Correspondence:
| | - Lisa Amelse
- Large Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Knoxville, TN 37996-4550, USA
| | - Austin Bow
- Large Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Knoxville, TN 37996-4550, USA
| | - Steven Newby
- Large Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Knoxville, TN 37996-4550, USA
| | - Amber MacDonald
- Large Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Knoxville, TN 37996-4550, USA
| | - Xiaocun Sun
- Office of Information and Technology, University of Tennessee, Knoxville, TN 37996, USA
| | - David Anderson
- Large Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Knoxville, TN 37996-4550, USA
| | - Madhu Dhar
- Large Animal Clinical Sciences, University of Tennessee College of Veterinary Medicine, Knoxville, TN 37996-4550, USA
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16
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Keeling LE, Belk JW, Kraeutler MJ, Kallner AC, Lindsay A, McCarty EC, Postma WF. Bone Marrow Aspirate Concentrate for the Treatment of Knee Osteoarthritis: A Systematic Review. Am J Sports Med 2022; 50:2315-2323. [PMID: 34236913 DOI: 10.1177/03635465211018837] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Bone marrow aspirate concentrate (BMAC) has emerged as a therapeutic option for symptomatic knee osteoarthritis (OA). PURPOSE To systematically review the literature to evaluate the efficacy of isolated BMAC injection in the treatment of OA of the knee joint. STUDY DESIGN Systematic review; Level of evidence, 4. METHODS A systematic review was performed by searching the PubMed, Embase, and Cochrane Library databases up to July 2020 to identify human studies that assessed the clinical outcomes of isolated BMAC injection for the treatment of knee OA. The electronic search strategy used was "bone marrow aspirate concentrate knee osteoarthritis." RESULTS Eight studies met the inclusion criteria, including a total of 299 knees with a mean follow-up of 12.9 months (range, 6-30 months). Of all patient-reported outcomes assessed across studies, 34 of 36 (94.4%) demonstrated significant improvement from baseline to latest follow-up (P < .05). Five studies evaluating numerical pain scores (visual analog scale and Numeric Rating Scale) reported significant improvements in pain level at final follow-up (P < .01). However, 3 comparative studies evaluating BMAC in relation to other therapeutic injections failed to demonstrate the clinical superiority of BMAC. CONCLUSION The BMAC injection is effective in improving pain and patient-reported outcomes in patients with knee OA at short- to midterm follow-up. Nevertheless, BMAC has not demonstrated clinical superiority in relation to other biologic therapies commonly used in the treatment of OA, including platelet-rich plasma and microfragmented adipose tissue, or in relation to placebo. The high cost of the BMAC injection in comparison with other biologic and nonoperative treatment modalities may limit its utility despite demonstrable clinical benefit.
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Affiliation(s)
- Laura E Keeling
- Department of Orthopaedics, MedStar Georgetown University Hospital, Washington, DC, USA
| | - John W Belk
- Department of Orthopedics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Matthew J Kraeutler
- Department of Orthopaedic Surgery, St Joseph's University Medical Center, Paterson, New Jersey, USA
| | | | - Adam Lindsay
- Department of Orthopedics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Eric C McCarty
- Department of Orthopedics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - William F Postma
- Department of Orthopaedics, MedStar Georgetown University Hospital, Washington, DC, USA
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17
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Arliani GG, Durigon TS, Pedroso JP, Ferreira GF, Oksman D, Oliveira VO. Infiltração intraarticular de plasma rico em plaquetas versus ácido hialurônico em pacientes com osteoartrose primária do joelho: Ensaio clínico randomizado com resultados preliminares. Rev Bras Ortop 2022; 57:402-408. [PMID: 35785122 PMCID: PMC9246520 DOI: 10.1055/s-0041-1724082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 09/17/2020] [Indexed: 11/29/2022] Open
Abstract
Objective
The present study aimed to compare the effects of intraarticular infiltration of platelet-rich plasma with those of hyaluronic acid infiltration in the treatment of patients with primary knee osteoarthritis.
Methods
A randomized clinical trial was conducted with 29 patients who received an intraarticular infiltration with hyaluronic acid (control group) or platelet-rich plasma. Clinical outcomes were assessed using the visual analog scale for pain and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire before and after the intervention. In addition, the posttreatment adverse effects were recorded. Categorical variables were analyzed using the chi-square and Fisher exact tests, whereas continuous variables were analyzed using the Student
t
test, analysis of variance, and the Wilcoxon test; all calculations were performed with the Stats package of the R software.
Results
An independent analysis of each group revealed a statistical difference within the first months, with improvement in the pain and function scores, but worsening on the 6
th
month after the procedure. There was no difference in the outcomes between the groups receiving hyaluronic acid or platelet-rich plasma. There was no serious adverse effect or allergic reaction during the entire follow-up period.
Conclusion
Intraarticular infiltration with hyaluronic acid or platelet-rich plasma in patients with primary knee gonarthrosis resulted in temporary improvement of functional symptoms and pain. There was no difference between interventions.
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Affiliation(s)
| | | | - João Paulo Pedroso
- Departamento de Ortopedia e Traumatologia, Instituto Prevent Senior, São Paulo, SP, Brasil
| | | | - Daniel Oksman
- Departamento de Ortopedia e Traumatologia, Instituto Prevent Senior, São Paulo, SP, Brasil
| | - Victor Otávio Oliveira
- Departamento de Ortopedia e Traumatologia, Instituto Prevent Senior, São Paulo, SP, Brasil
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18
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Bhogoju S, Khan S, Subramanian A. Continuous Low-Intensity Ultrasound Preserves Chondrogenesis of Mesenchymal Stromal Cells in the Presence of Cytokines by Inhibiting NFκB Activation. Biomolecules 2022; 12:434. [PMID: 35327626 PMCID: PMC8946190 DOI: 10.3390/biom12030434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/21/2022] [Accepted: 03/03/2022] [Indexed: 02/04/2023] Open
Abstract
Proinflammatory joint environment, coupled with impeded chondrogenic differentiation of mesenchymal stromal cells (MSCs), led to inferior cartilage repair outcomes. Nuclear translocation of phosphorylated-NFκB downregulates SOX9 and hinders the chondrogenesis of MSCs. Strategies that minimize the deleterious effects of NFκB, while promoting MSC chondrogenesis, are of interest. This study establishes the ability of continuous low-intensity ultrasound (cLIUS) to preserve MSC chondrogenesis in a proinflammatory environment. MSCs were seeded in alginate:collagen hydrogels and cultured for 21 days in an ultrasound-assisted bioreactor (5.0 MHz, 2.5 Vpp; 4 applications/day) in the presence of IL1β and evaluated by qRT-PCR and immunofluorescence. The differential expression of markers associated with the NFκB pathway was assessed upon a single exposure of cLIUS and assayed by Western blotting, qRT-PCR, and immunofluorescence. Mitochondrial potential was evaluated by tetramethylrhodamine methyl ester (TMRM) assay. The chondroinductive potential of cLIUS was noted by the increased expression of SOX9 and COLII. cLIUS extended its chondroprotective effects by stabilizing the NFκB complex in the cytoplasm via engaging the IκBα feedback mechanism, thus preventing its nuclear translocation. cLIUS acted as a mitochondrial protective agent by restoring the mitochondrial potential and the mitochondrial mRNA expression in a proinflammatory environment. Altogether, our results demonstrated the potential of cLIUS for cartilage repair and regeneration under proinflammatory conditions.
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Affiliation(s)
| | | | - Anuradha Subramanian
- Department of Chemical and Materials Engineering, The University of Alabama in Huntsville, Huntsville, AL 35899, USA; (S.B.); (S.K.)
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19
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Hemati K, Pourhanifeh MH, Fatemi I, Hosseinzadeh A, Mehrzadi S. Anti-degenerative effect of melatonin on intervertebral disc: protective contribution against inflammation, oxidative stress, apoptosis, and autophagy. Curr Drug Targets 2022; 23:711-718. [PMID: 35034592 DOI: 10.2174/1389450123666220114151654] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 10/08/2021] [Accepted: 12/01/2021] [Indexed: 11/22/2022]
Abstract
Intervertebral disc (IVD) degeneration is a leading cause of lower back pain. Although the etiology of IVD degeneration (IVDD) is unclear, excessive oxidative stress, inflammation and apoptosis and disruption of autophagy play important role in the pathogenesis of IVDD. Therefore, finding a solution to mitigate these processes could stop or reduce the development of IVDD. Melatonin, a powerful antioxidant, plays an important role in regulating cartilage tissue hemostasis. Melatonin inhibits destruction of extracellular matrix (ECM) of disc. Melatonin preserves ECM contents including sox-9, aggrecan, and collagen II through inhibiting matrix degeneration enzymes such as MMP-13. These protective effects may be mediated by the inhibition of oxidative stress, inflammation and apoptosis, and regulation of autophagy in IVD cells.
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Affiliation(s)
- Karim Hemati
- Department of Anesthesiology, Iran University of Medical Sciences, Tehran, Iran
| | | | - Iman Fatemi
- Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman, Iran
| | - Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
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20
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Leonardi EA, Xiao M, Murray IR, Robinson WH, Abrams GD. Tendon-Derived Progenitor Cells With Multilineage Potential Are Present Within Human Patellar Tendon. Orthop J Sports Med 2021; 9:23259671211023452. [PMID: 34435068 PMCID: PMC8381435 DOI: 10.1177/23259671211023452] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 02/24/2021] [Indexed: 01/13/2023] Open
Abstract
Background: Progenitor cells serve as a promising source of regenerative potential in a
variety of tissue types yet remain underutilized in tendinopathy.
Tendon-derived progenitor cells (TDPCs) have previously been isolated from
hamstring tendon but only as part of a concomitant medical procedure.
Determining the presence of TDPCs in patellar tendon may facilitate clinical
utilization of these cells because of the relative accessibility of this
location for tissue harvest. Purpose: To characterize TDPCs in human patellar tendon samples. Study Design: Descriptive laboratory study. Methods: Human patellar tendon samples were obtained during elective knee surgery.
TDPCs were isolated and seeded at an optimal low cell density and
subcultured to confluence for up to 2 passages. Flow cytometry was used to
analyze for the expression of CD90+, CD105+, CD44+, and CD31–, CD34–, and
CD45– markers. The multilineage differentiation potential of TDPCs was
tested in vitro via adipogenic, osteogenic, and chondrogenic culture with
subsequent cytochemical staining for Oil Red O, Alizarin Red, and Alcian
Blue, respectively. Enzyme-linked immunosorbent assay was used to quantify
the amount of adiponectin, alkaline phosphatase, and SRY-box transcription
factor 9 secreted into cell culture supernatant for further confirmation of
lineage differentiation. Results were analyzed statistically using the
2-tailed Student t test. Results: TDPCs demonstrated near-uniform expression of CD90, CD105, and CD44 with
minimal expression of CD34, CD31, and CD45. Adipogenic, osteogenic, and
chondrogenic differentiation of TDPCs was confirmed using qualitative
analysis. The expression of adiponectin, alkaline phosphatase, and SRY-box
transcription factor 9 were significantly increased in differentiated cells
versus undifferentiated TDPCs (P < .05). Conclusion: TDPCs can be successfully isolated from human patellar tendon samples, and
they exhibit characteristics of multipotent progenitor cells. Clinical Relevance: These data demonstrate the promise of patellar tendon tissue as a source of
progenitor cells for use in biologic therapies for the treatment of
tendinopathy.
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Affiliation(s)
- Erika A Leonardi
- Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Michelle Xiao
- Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Iain R Murray
- Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - William H Robinson
- Division of Rheumatology and Immunology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.,Palo Alto Division, VA Palo Alto Health Care System, Palo Alto, California, USA
| | - Geoffrey D Abrams
- Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford, California, USA
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Lee NH, Na SM, Ahn HW, Kang JK, Seon JK, Song EK. Allogenic Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Are More Effective Than Bone Marrow Aspiration Concentrate for Cartilage Regeneration After High Tibial Osteotomy in Medial Unicompartmental Osteoarthritis of Knee. Arthroscopy 2021; 37:2521-2530. [PMID: 33621649 DOI: 10.1016/j.arthro.2021.02.022] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 02/02/2023]
Abstract
PURPOSE The purpose of this study was to compare the outcome of cartilage regeneration between bone marrow aspirate concentrate (BMAC) augmentation and allogeneic human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSCs) transplantation in high tibial osteotomy (HTO) with microfracture (MFX) for medial unicompartmental osteoarthritis (OA) of the knee in the young and active patient. METHODS Between January 2015 and December 2019, the patients who underwent HTO and arthroscopy with MFX combined with BMAC or allogeneic hUCB-MSCs procedure for medial unicompartmental OA with kissing lesion, which was shown full-thickness cartilage defect (≥ International Cartilage Repair Society [ICRS] grade 3B) in medial femoral cartilage and medial tibial cartilage, were include in this study. Retrospectively we compared clinical outcomes, including Hospital for Special Surgery score, Knee Society Score (KSS) pain and function, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score between BMAC and hUCB-MSCs group at minimum of 1-year follow-up. Also, second-look arthroscopy was performed simultaneously with removal of the plate after complete bone union. Cartilage regeneration was graded by the ICRS grading system at second-look arthroscopy. Radiological measurement including hip-knee-ankle (HKA) angle, posterior tibial slope angle, and correction angle were assessed. RESULTS Of 150 cases that underwent HTO with MFX combined with BMAC or allogeneic hUCB-MSCs procedure for medial unicompartmental OA, 123 cases underwent plate removal and second-look arthroscopy after a minimum of 1 year after the HTO surgery. Seventy-four cases were kissing lesion in medial femoral cartilage and medial tibial cartilage during initial HTO surgery. Finally, the BMAC group composed of 42 cases and hUCB-MSCs group composed of 32 cases were retrospectively identified in patients who had kissing lesions and second-look arthroscopies with a minimum of 1 year of follow-up. At the final follow-up of mean 18.7 months (standard deviation = 4.6 months), clinical outcomes in both groups had improved. However, there were no significant differences between the IKDC, WOMAC, or KSS pain and function scores in the 2 groups (P > .05). At second-look arthroscopy, the ICRS grade was significantly better in the hUCB-MSC group than in the BMAC group in both medial femoral and medial tibial cartilage (P = .001 for both). The average ICRS grade of the BMAC group improved from 3.9 before surgery to 2.8 after surgery. The average ICRS grade of the hUBC-MSC group improved from 3.9 before surgery to 2.0 after surgery. Radiological findings comparing postoperative HKA angle, posterior tibial slope angle, and correction angle showed no significant differences between the groups (P > .05). Therefore it was found that the postoperative correction amount did not affect the postoperative cartilage regeneration results. CONCLUSIONS We found that the hUCB-MSC procedure was more effective than the BMAC procedure for cartilage regeneration in medial unicompartmental knee OA even though the clinical outcomes improved regardless of which treatment was administered. LEVEL OF EVIDENCE Level III, retrospective comparative study.
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Affiliation(s)
- Nam-Hun Lee
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea
| | - Seung-Min Na
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea
| | - Hyeon-Wook Ahn
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea
| | - Joon-Kyoo Kang
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea
| | - Jong-Keun Seon
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea.
| | - Eun-Kyoo Song
- Department of Orthopaedic Surgery, Chonnam National University Medical School and Hospital, Hwasun, Republic of Korea
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22
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Drzeniek NM, Mazzocchi A, Schlickeiser S, Forsythe SD, Moll G, Geißler S, Reinke P, Gossen M, Gorantla VS, Volk HD, Soker S. Bio-instructive hydrogel expands the paracrine potency of mesenchymal stem cells. Biofabrication 2021; 13:10.1088/1758-5090/ac0a32. [PMID: 34111862 PMCID: PMC10024818 DOI: 10.1088/1758-5090/ac0a32] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 06/10/2021] [Indexed: 02/03/2023]
Abstract
The therapeutic efficacy of clinically applied mesenchymal stromal cells (MSCs) is limited due to their injection into harshin vivoenvironments, resulting in the significant loss of their secretory function upon transplantation. A potential strategy for preserving their full therapeutic potential is encapsulation of MSCs in a specialized protective microenvironment, for example hydrogels. However, commonly used injectable hydrogels for cell delivery fail to provide the bio-instructive cues needed to sustain and stimulate cellular therapeutic functions. Here we introduce a customizable collagen I-hyaluronic acid (COL-HA)-based hydrogel platform for the encapsulation of MSCs. Cells encapsulated within COL-HA showed a significant expansion of their secretory profile compared to MSCs cultured in standard (2D) cell culture dishes or encapsulated in other hydrogels. Functionalization of the COL-HA backbone with thiol-modified glycoproteins such as laminin led to further changes in the paracrine profile of MSCs. In depth profiling of more than 250 proteins revealed an expanded secretion profile of proangiogenic, neuroprotective and immunomodulatory paracrine factors in COL-HA-encapsulated MSCs with a predicted augmented pro-angiogenic potential. This was confirmed by increased capillary network formation of endothelial cells stimulated by conditioned media from COL-HA-encapsulated MSCs. Our findings suggest that encapsulation of therapeutic cells in a protective COL-HA hydrogel layer provides the necessary bio-instructive cues to maintain and direct their therapeutic potential. Our customizable hydrogel combines bioactivity and clinically applicable properties such as injectability, on-demand polymerization and tissue-specific elasticity, all features that will support and improve the ability to successfully deliver functional MSCs into patients.
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Affiliation(s)
- Norman M Drzeniek
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany.,Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Andrea Mazzocchi
- Known Medicine Inc., 675 Arapeen Dr, Suite 103A-1, Salt Lake City, UT 84108, United States of America.,Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States of America
| | - Stephan Schlickeiser
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany
| | - Steven D Forsythe
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States of America
| | - Guido Moll
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany.,Berlin-Brandenburg School for Regenerative Therapies (BSRT), Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Sven Geißler
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany.,Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany.,Berlin Center for Advanced Therapies (BeCAT), Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Manfred Gossen
- Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.,Institute of Active Polymers, Helmholtz-Zentrum Hereon, Kantstr. 55, Teltow 14513, Germany
| | - Vijay S Gorantla
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States of America
| | - Hans-Dieter Volk
- Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, Germany
| | - Shay Soker
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, United States of America
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23
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Notch-Wnt signal crosstalk regulates proliferation and differentiation of osteoprogenitor cells during intramembranous bone healing. NPJ Regen Med 2021; 6:29. [PMID: 34050174 PMCID: PMC8163848 DOI: 10.1038/s41536-021-00139-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 05/10/2021] [Indexed: 02/06/2023] Open
Abstract
Adult bone regeneration is orchestrated by the precise actions of osteoprogenitor cells (OPCs). However, the mechanisms by which OPC proliferation and differentiation are linked and thereby regulated are yet to be defined. Here, we present evidence that during intramembranous bone formation OPC proliferation is controlled by Notch signaling, while differentiation is initiated by activation of canonical Wnt signaling. The temporospatial separation of Notch and Wnt signal activation during the early stages of bone regeneration suggests crosstalk between the two pathways. In vitro and in vivo manipulation of the two essential pathways demonstrate that Wnt activation leads to initiation of osteogenic differentiation and at the same time inhibits Notch signaling, which results in termination of the proliferative phase. Here, we establish canonical Wnt signaling as a key regulator that facilitates the crosstalk between OPC proliferation and differentiation during intramembranous, primary bone healing.
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Amodeo G, Niada S, Moschetti G, Franchi S, Savadori P, Brini AT, Sacerdote P. Secretome of human adipose-derived mesenchymal stem cell relieves pain and neuroinflammation independently of the route of administration in experimental osteoarthritis. Brain Behav Immun 2021; 94:29-40. [PMID: 33737173 DOI: 10.1016/j.bbi.2021.03.011] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Treatment of pain associated with osteoarthritis (OA) is unsatisfactory and innovative approaches are needed. The secretome from human adipose-derived mesenchymal stem cells (hASC-Conditioned Medium, CM) has been successfully used to relieve painful symptoms in models of chronic pain. The aim of this study was to explore the efficacy of the hASC-CM to control pain and neuroinflammation in an animal model of OA. METHODS OA was induced in mice by intra-articular monosodium-iodoacetate (MIA) injection. Thermal hyperalgesia and mechanical allodynia were assessed. Once hypersensitivity was established (7 days after MIA), hASC-CM was injected by IA, IPL and IV route and its effect monitored over time. Neuroinflammation in nerve, dorsal root ganglia and spinal cord was evaluated measuring proinflammatory markers and mediators by RT-qPCR. Protein content analysis of secretome by Mass Spectrometry was performed. RESULTS A single injection with hASC-CM induced a fast and long lasting antihyperalgesic and antiallodynic effect. The IV route of administration appeared to be the most efficacious although all the treatments were effective. The effect on pain correlated with the ability of hASC-CM to reduce the neuroinflammatory condition in both the peripheral and central nervous system. Furthermore, the secretome analysis revealed 101 factors associated with immune regulation. CONCLUSION We suggest that hASC-CM is a valid treatment option for controlling OA-related hypersensitivity, exerting a rapid and long lasting pain relief. The mechanisms underpinning its effects are likely linked to the positive modulation of neuroinflammation in peripheral and central nervous system that sustains peripheral and central sensitization.
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Affiliation(s)
- Giada Amodeo
- Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milano, Milano, Italy
| | | | - Giorgia Moschetti
- Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milano, Milano, Italy
| | - Silvia Franchi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milano, Milano, Italy
| | | | - Anna T Brini
- IRCCS Istituto Ortopedico Galeazzi, Milano, Italy; Dipartimento di Scienze Biomediche Chirurgiche e Odontoiatriche, University of Milano, Milano, Italy
| | - Paola Sacerdote
- Dipartimento di Scienze Farmacologiche e Biomolecolari, University of Milano, Milano, Italy.
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25
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Kruel AVS, Ribeiro LL, Gusmão PD, Huber SC, Lana JFSD. Orthobiologics in the treatment of hip disorders. World J Stem Cells 2021; 13:304-316. [PMID: 33959220 PMCID: PMC8080542 DOI: 10.4252/wjsc.v13.i4.304] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/26/2020] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Orthobiologics are biological materials that are intended for the regeneration or healing of bone, cartilage and soft tissues. In this review we discuss the use of orthobiologics for hip disorders providing an update. The orthobiologics included in this article are hyaluronic acid, platelet rich plasma, bone marrow, adipose tissue and expanded mesenchymal stem cells. We explain the concepts and definitions of each orthobiological product, and the literature regarding its use in the hip joint. The paucity of guidelines for the production and characterization of the biological products leads to uneven results across the literature. Each biologic therapy has indications and benefits; however, noteworthy are the characterization of the orthobiologics, the application method and outcome analysis for further improvement of each technique.
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Affiliation(s)
| | - Lucas Leite Ribeiro
- Department of Orthopedics, Instituto Médico Salus, São Paulo, SP 01308-050, Brazil
| | - Paulo David Gusmão
- Department of Orthopedics, the Bone and Cartilage Institute, Porto Alegre, RS 90570-020, Brazil
| | - Stephany Cares Huber
- Department of Hematology, University of Campinas, Campinas, SP 13334-170, Brazil
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26
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Abstract
BACKGROUND This manuscript is a review of the literature investigating the use of mesenchymal stem cells (MSCs) being applied in the setting of spinal fusion surgery. We mention the rates of pseudarthrosis, discuss current bone grafting options, and examine the preclinical and clinical outcomes of utilizing MSCs to assist in successfully fusing the spine. METHODS A thorough literature review was conducted to look at current and previous preclinical and clinical studies using stem cells for spinal fusion augmentation. Searches for PubMed/MEDLINE and ClinicalTrials.gov through January 2021 were conducted for literature mentioning stem cells and spinal fusion. RESULTS All preclinical and clinical studies investigating MSC use in spinal fusion were examined. We found 19 preclinical and 17 clinical studies. The majority of studies, both preclinical and clinical, were heterogeneous in design due to different osteoconductive scaffolds, cells, and techniques used. Preclinical studies showed promising outcomes in animal models when using appropriate osteoconductive scaffolds and factors for osteogenic differentiation. Similarly, clinical studies have promising outcomes but differ in their methodologies, surgical techniques, and materials used, making it difficult to adequately compare between the studies. CONCLUSION MSCs may be a promising option to use to augment grafting for spinal fusion surgery. MSCs must be used with appropriate osteoconductive scaffolds. Cell-based allografts and the optimization of their use have yet to be fully elucidated. Further studies are necessary to determine the efficacy of MSCs with different osteoconductive scaffolds and growth/osteogenic differentiation factors. LEVEL OF EVIDENCE 3.
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Affiliation(s)
- Stephen R Stephan
- Department of Orthopaedic Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Linda E Kanim
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Hyun W Bae
- Department of Orthopaedic Surgery, Cedars-Sinai Medical Center, Los Angeles, California.,Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
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27
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Fernández-Francos S, Eiro N, Costa LA, Escudero-Cernuda S, Fernández-Sánchez ML, Vizoso FJ. Mesenchymal Stem Cells as a Cornerstone in a Galaxy of Intercellular Signals: Basis for a New Era of Medicine. Int J Mol Sci 2021; 22:ijms22073576. [PMID: 33808241 PMCID: PMC8036553 DOI: 10.3390/ijms22073576] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023] Open
Abstract
Around 40% of the population will suffer at some point in their life a disease involving tissue loss or an inflammatory or autoimmune process that cannot be satisfactorily controlled with current therapies. An alternative for these processes is represented by stem cells and, especially, mesenchymal stem cells (MSC). Numerous preclinical studies have shown MSC to have therapeutic effects in different clinical conditions, probably due to their mesodermal origin. Thereby, MSC appear to play a central role in the control of a galaxy of intercellular signals of anti-inflammatory, regenerative, angiogenic, anti-fibrotic, anti-oxidative stress effects of anti-apoptotic, anti-tumor, or anti-microbial type. This concept forces us to return to the origin of natural physiological processes as a starting point to understand the evolution of MSC therapy in the field of regenerative medicine. These biological effects, demonstrated in countless preclinical studies, justify their first clinical applications, and draw a horizon of new therapeutic strategies. However, several limitations of MSC as cell therapy are recognized, such as safety issues, handling difficulties for therapeutic purposes, and high economic cost. For these reasons, there is an ongoing tendency to consider the use of MSC-derived secretome products as a therapeutic tool, since they reproduce the effects of their parent cells. However, it will be necessary to resolve key aspects, such as the choice of the ideal type of MSC according to their origin for each therapeutic indication and the implementation of new standardized production strategies. Therefore, stem cell science based on an intelligently designed production of MSC and or their derivative products will be able to advance towards an innovative and more personalized medical biotechnology.
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Affiliation(s)
| | - Noemi Eiro
- Research Unit, Fundación Hospital de Jove, 33290 Gijón, Spain; (S.F.-F.); (L.A.C.)
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-985320050 (ext. 84216)
| | - Luis A. Costa
- Research Unit, Fundación Hospital de Jove, 33290 Gijón, Spain; (S.F.-F.); (L.A.C.)
| | - Sara Escudero-Cernuda
- Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, 33006 Oviedo, Spain; (S.E.-C.); (M.L.F.-S.)
| | - María Luisa Fernández-Sánchez
- Department of Physical and Analytical Chemistry, Faculty of Chemistry, University of Oviedo, 33006 Oviedo, Spain; (S.E.-C.); (M.L.F.-S.)
| | - Francisco J. Vizoso
- Research Unit, Fundación Hospital de Jove, 33290 Gijón, Spain; (S.F.-F.); (L.A.C.)
- Correspondence: (N.E.); (F.J.V.); Tel.: +34-985320050 (ext. 84216)
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28
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van de Peppel J, Schaaf GJ, Matos AA, Guo Y, Strini T, Verschoor W, Dudakovic A, van Wijnen AJ, van Leeuwen JPTM. Cell Surface Glycoprotein CD24 Marks Bone Marrow-Derived Human Mesenchymal Stem/Stromal Cells with Reduced Proliferative and Differentiation Capacity In Vitro. Stem Cells Dev 2021; 30:325-336. [PMID: 33593128 DOI: 10.1089/scd.2021.0027] [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] [Indexed: 01/01/2023] Open
Abstract
Bone marrow-derived mesenchymal stem/stromal cells (BMSCs) are fundamental to bone regenerative therapies, tissue engineering, and postmenopausal osteoporosis. Donor variation among patients, cell heterogeneity, and unpredictable capacity for differentiation reduce effectiveness of BMSCs for regenerative cell therapies. The cell surface glycoprotein CD24 exhibits the most prominent differential expression during osteogenic versus adipogenic differentiation of human BMSCs. Therefore, CD24 may represent a selective biomarker for subpopulations of BMSCs with increased osteoblastic potential. In undifferentiated human BMSCs, CD24 cell surface expression is variable among donors (range: 2%-10%) and increased by two to fourfold upon osteogenic differentiation. Strikingly, FACS sorted CD24pos cells exhibit delayed mineralization and reduced capacity for adipocyte differentiation. RNAseq analysis of CD24pos and CD24neg BMSCs identified a limited number of genes with increased expression in CD24pos cells that are associated with cell adhesion, motility, and extracellular matrix. Downregulated genes are associated with cell cycle regulation, and biological assays revealed that CD24pos cells have reduced proliferation. Hence, expression of the cell surface glycoprotein CD24 identifies a subpopulation of human BMSCs with reduced capacity for proliferation and extracellular matrix mineralization. Functional specialization among BMSCs populations may support their regenerative potential and therapeutic success by accommodating cell activities that promote skeletal tissue formation, homeostasis, and repair.
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Affiliation(s)
- Jeroen van de Peppel
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Gerben J Schaaf
- Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Adriana Arruda Matos
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Yuan Guo
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Tanja Strini
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Wenda Verschoor
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Amel Dudakovic
- Department of Orthopedic Surgery, and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
| | - Andre J van Wijnen
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.,Department of Orthopedic Surgery, and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
| | - Johannes P T M van Leeuwen
- Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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29
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Shehadi JA, Elzein SM, Beery P, Spalding MC, Pershing M. Combined administration of platelet rich plasma and autologous bone marrow aspirate concentrate for spinal cord injury: a descriptive case series. Neural Regen Res 2021; 16:362-366. [PMID: 32859799 PMCID: PMC7896202 DOI: 10.4103/1673-5374.290903] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Administration of platelet rich plasma (PRP) and bone marrow aspirate concentrate (BMAC) has shown some promise in the treatment of neurological conditions; however, there is limited information on combined administration. As such, the purpose of this study was to assess safety and functional outcomes for patients administered combined autologous PRP and BMAC for spinal cord injury (SCI). This retrospective case series included seven patients who received combined treatment of autologous PRP and BMAC via intravenous and intrathecal administration as salvage therapy for SCI. Patients were reviewed for adverse reactions and clinical outcomes using the Oswestry Disability Index (ODI) for up to 1 year, as permitted by availability of follow-up data. Injury levels ranged from C3 through T11, and elapsed time between injury and salvage therapy ranged from 2.4 months to 6.2 years. Post-procedure complications were mild and rare, consisting only of self-limited headache and subjective memory impairment in one patient. Four patients experienced severe disability prior to PRP combined with BMAC injection, as evidenced by high (> 48/100) Oswestry Disability Index scores. Longitudinal Oswestry Disability Index scores for two patients with incomplete SCI at C6 and C7, both of whom had cervical spine injuries, demonstrated a decrease of 28–40% following salvage therapy, representing an improvement from severe to minimal disability. In conclusion, intrathecal/intravenous co-administration of PRP and BMAC resulted in no significant complications and may have had some clinical benefits. Larger clinical studies are needed to further test this method of treatment for patients with SCI who otherwise have limited meaningful treatment options. This study was reviewed and approved by the OhioHealth Institutional Review Board (IRB No. 1204946) on May 16, 2018.
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Affiliation(s)
- Joseph A Shehadi
- Section of Neurosurgery at OhioHealth Grant Medical Center, Cedar Stem Cell Institute, Columbus, OH, USA
| | - Steven M Elzein
- The Ohio State University College of Medicine, Columbus, OH, USA
| | - Paul Beery
- Division of Trauma and Acute Care Surgery, OhioHealth Grant Medical Center, Columbus, OH, USA
| | - M Chance Spalding
- Division of Trauma and Acute Care Surgery, OhioHealth Grant Medical Center, Columbus, OH, USA
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30
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Kubrova E, Su M, Galeano-Garces C, Galvan ML, Jerez S, Dietz AB, Smith J, Qu W, van Wijnen AJ. Differences in Cytotoxicity of Lidocaine, Ropivacaine, and Bupivacaine on the Viability and Metabolic Activity of Human Adipose-Derived Mesenchymal Stem Cells. Am J Phys Med Rehabil 2021; 100:82-91. [PMID: 32657816 PMCID: PMC11784493 DOI: 10.1097/phm.0000000000001529] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE We evaluated biological effects of distinct local anesthetics on human adipose-derived mesenchymal stem cells when applied to reduce periprocedural pain during mesenchymal stem cell injections. METHODS AND MATERIALS Metabolic activity (MTS assay), viability (Live/Dead stain), and gene expression (quantitative real-time reverse-transcriptase polymerase chain reaction) were measured in mesenchymal stem cells incubated with various concentrations of lidocaine, ropivacaine, or bupivacaine during a 12-hr time course. RESULTS Cell viability and metabolic activity decreased in a dose, time, and substance-specific manner after exposure to lidocaine, ropivacaine, and bupivacaine, with ropivacaine being the least cytotoxic. Cell viability decreases after brief exposure (<1.5 hrs) at clinically relevant concentrations (eg, 8 mg/ml of lidocaine, 2.5 mg/ml of ropivacaine or bupivacaine). Mesenchymal stem cells exposed to local anesthetics change their expression of mRNA biomarkers for stress response (EGR1, EGR2), proliferation (MKI67, HIST2H4A), ECM (COL1A1, COL3A1), and cell surface marker (CD105). CONCLUSIONS Local anesthetics are cytotoxic to clinical-grade human mesenchymal stem cells in a dose-, time-, and agent-dependent manner and change expression of ECM, proliferation, and cell surface markers. Lidocaine and bupivacaine are more cytotoxic than ropivacaine. Single-dose injections of local anesthetics may affect the biological properties of mesenchymal stem cells in vitro but may not affect the effective dose of MSCs in a clinical setting.
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Affiliation(s)
- Eva Kubrova
- From the Department of Physical Medicine & Rehabilitation, Mayo Clinic, Rochester, Minnesota (EK, MS, JS, WQ); Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota (EK, MS, CG-G, MLG, SJ, AJvW); Department of Biochemistry & Molecular Biology, Mayo Clinic, Rochester, Minnesota (MS, CG-G, SJ, AJvW); Department of Physical Medicine & Rehabilitation, The First Affiliated Hospital of Soochow University, Suzhou, China (MS); and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (ABD)
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31
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Anastasio A, Gergues M, Lebhar MS, Rameshwar P, Fernandez-Moure J. Isolation and characterization of mesenchymal stem cells in orthopaedics and the emergence of compact bone mesenchymal stem cells as a promising surgical adjunct. World J Stem Cells 2020; 12:1341-1353. [PMID: 33312402 PMCID: PMC7705465 DOI: 10.4252/wjsc.v12.i11.1341] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 09/26/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
The potential clinical and economic impact of mesenchymal stem cell (MSC) therapy is immense. MSCs act through multiple pathways: (1) as “trophic” cells, secreting various factors that are immunomodulatory, anti-inflammatory, anti-apoptotic, proangiogenic, proliferative, and chemoattractive; (2) in conjunction with cells native to the tissue they reside in to enhance differentiation of surrounding cells to facilitate tissue regrowth. Researchers have developed methods for the extraction and expansion of MSCs from animal and human tissues. While many sources of MSCs exist, including adipose tissue and iliac crest bone graft, compact bone (CB) MSCs have shown great potential for use in orthopaedic surgery. CB MSCs exert powerful immunomodulatory effects in addition to demonstrating excellent regenerative capacity for use in filling boney defects. CB MSCs have been shown to have enhanced response to hypoxic conditions when compared with other forms of MSCs. More work is needed to continue to characterize the potential applications for CB MSCs in orthopaedic trauma.
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Affiliation(s)
- Albert Anastasio
- Department of Orthopedic Surgery, Duke University Health System, Durham, NC 27710, United States
| | - Marina Gergues
- Department of Medicine, Hematology/Oncology, Rutgers University, New Jersey Medical School, Newark, NJ 07103, United States
| | - Michael S Lebhar
- School of Medicine, Duke University School of Medicine, Durham, NC 27710, United States
| | - Pranela Rameshwar
- Department of Medicine-Hematology/Oncology, Rutgers School of Biomedical Health Science, Newark, NJ 07103, United States
| | - Joseph Fernandez-Moure
- Department of Surgery, Division of Trauma, Acute, and Critical Care Surgery, Duke University School of Medicine, Durham, NC 27710, United States
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Shin MJ, Shim IK, Kim DM, Choi JH, Lee YN, Jeon IH, Kim H, Park D, Kholinne E, Yang HS, Koh KH. Engineered Cell Sheets for the Effective Delivery of Adipose-Derived Stem Cells for Tendon-to-Bone Healing. Am J Sports Med 2020; 48:3347-3358. [PMID: 33136454 DOI: 10.1177/0363546520964445] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Efforts are being made to treat rotator cuff tears (RCTs) that exhibit poor healing and high retear rates. Tendon-to-bone healing using mesenchymal stem cells is being explored, but research is needed to establish effective delivery options. PURPOSE To evaluate the effects of an adipose-derived stem cell (ADSC) sheet on mesenchymal stem cell delivery for tendon-to-bone healing of a chronic RCT in rats and to demonstrate that ADSC sheets enhance tendon-to-bone healing. STUDY DESIGN Controlled laboratory study. METHODS Mesenchymal stem cells were obtained from rat adipose tissue, and a cell sheet was prepared using a temperature-responsive dish. To evaluate the efficacy of stem cells produced in a sheet for the lesion, the experiment was conducted with 3 groups: repair group, cell sheet transplantation after repair group, and cell sheet-only group. Histological, biomechanical, and micro-computed tomography (micro-CT) results were compared among the groups. RESULTS Hematoxylin and eosin staining for histomorphological analysis revealed that the cell sheet transplantation after repair group (5.75 ± 0.95) showed statistically significant higher scores than the repair (2.75 ± 0.50) and cell sheet-only (3.25 ± 0.50) groups (P < .001). On safranin O staining, the cell sheet transplantation after repair group (0.51 ± 0.04 mm2) had a larger fibrocartilage area than the repair (0.31 ± 0.06 mm2) and cell sheet-only (0.32 ± 0.03 mm2) groups (P = .001). On micro-CT, bone volume/total volume values were significantly higher in the cell sheet transplantation after repair group (23.98% ± 1.75%) than in the other groups (P < .039); there was no significant difference in the other values. On the biomechanical test, the cell sheet transplantation after repair group (4 weeks after repair) showed significantly higher results than the other groups (P < .005). CONCLUSION Our study shows that engineered stem cells are a clinically feasible stem cell delivery tool for rotator cuff repair. CLINICAL RELEVANCE This laboratory study provides evidence that ADSCs are effective in repairing RCTs, which are common sports injuries.
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Affiliation(s)
- Myung Jin Shin
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In Kyong Shim
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong Min Kim
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae Hee Choi
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.,Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yu Na Lee
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In-Ho Jeon
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyojune Kim
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dongjun Park
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Erica Kholinne
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.,Department of Orthopedic Surgery, St Carolus Hospital, Faculty of Medicine, Trisakti University, Jakarta, Indonesia
| | - Ha-Sol Yang
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyoung Hwan Koh
- Department of Orthopedic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Ahmed RY, Elsherbini AM, Elkhier MTA, Soussa EF. A comparison of the early therapeutic effects of allogeneic bone marrow-derived mesenchymal stem cells and calcitonin on the healing of surgically induced mandibular bone defects in osteoporotic rats. Arch Oral Biol 2020; 120:104934. [PMID: 33091660 DOI: 10.1016/j.archoralbio.2020.104934] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 09/25/2020] [Accepted: 09/26/2020] [Indexed: 11/18/2022]
Abstract
OBJECTIVES This study aimed to evaluate and compare the early biological effects of allogeneic bone marrow-derived mesenchymal stem cells (BMSCs) versus salmon calcitonin (SC) on healing of surgically induced mandibular bone defects in osteoporotic rats. METHODS Sixty-one female albino rats were included in this study, four of them were used for BMSCs isolation. The remaining 57 rats were divided into 4 groups. Group I (negative control), 12 rats received a vehicle injection after which a unilateral mandibular defect was created in each rat. Osteoporosis was induced in the remaining 45 rats then rats were randomly allocated into 3 equal groups (15 each). Surgical defects were created as in group I. The defects were left to heal spontaneously in group II; positive control. While in group III each defect was filled with an absorbable hemostatic gelatin sponge loaded by 10 IU of injectable SC and in group IV the sponge was seeded by 0.5 × 106 BMSCs. Rats were euthanized at 1st, 2nd, and 4th week postsurgically. Hematoxylin and eosin, Masson's trichrome, picrosirius, and alizarin red s stains were used, followed by statistical analysis. RESULTS BMSCs-treatment showed marked enhanced bone healing. Moreover, collagen fibers and calcium deposits area percentages were statistically significantly higher when compared to the other groups particularly at 2 and 4 weeks. CONCLUSIONS Local application of bone marrow-derived mesenchymal stem cells and salmon calcitonin may be an effective therapy for treatment of osteoporotic bone defects, with privilege to the stem cells in terms of quantity and quality of regenerated bone.
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Affiliation(s)
- Rana Y Ahmed
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
| | - Amira M Elsherbini
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt.
| | - Mazen Th Abou Elkhier
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
| | - Essam F Soussa
- Department of Oral Biology, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
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Osteogenic and Anti-Inflammatory Behavior of Injectable Calcium Phosphate Loaded with Therapeutic Drugs. NANOMATERIALS 2020; 10:nano10091743. [PMID: 32899225 PMCID: PMC7558013 DOI: 10.3390/nano10091743] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 08/25/2020] [Accepted: 09/01/2020] [Indexed: 12/31/2022]
Abstract
Bone fractures related to musculoskeletal disorders determine long-term disability in older people with a consequent significant economic burden. The recovery of pathologically impaired tissue architecture allows avoiding bone loss-derived consequences such as bone height reduction, deterioration of bone structure, inflamed bone pain, and high mortality for thighbone fractures. Actually, standard therapy for osteoporosis treatment is based on the systemic administration of biphosphonates and anti-inflammatory drugs, which entail several side effects including gastrointestinal (GI) diseases, fever, and articular pain. Hence, the demand of innovative therapeutic approaches for locally treating bone lesions has been increasing in the last few years. In this scenario, the development of injectable materials loaded with therapeutically active agents (i.e., anti-inflammatory drugs, antibiotics, and peptides mimicking growth factors) could be an effective tool to treat bone loss and inflammation related to musculoskeletal diseases, including osteoporosis and osteoarthritis. According to this challenge, here, we propose three different compositions of injectable calcium phosphates (CaP) as new carrier materials of therapeutic compounds such as bisphosphonates (i.e., alendronate), anti-inflammatory drugs (i.e., diclofenac sodium), and natural molecules (i.e., harpagoside) for the local bone disease treatment. Biological quantitative analyses were performed for screening osteoinductive and anti-inflammatory properties of injectable drug-loaded systems. Meanwhile, cell morphological features were analyzed through scanning electron microscopy and confocal investigations. The results exhibited that the three systems exerted an osteoinductive effect during later phases of osteogenesis. Simultaneously, all compositions showed an anti-inflammatory activity on inflammation in vitro models.
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Mesenchymal Stem/Progenitor Cells: The Prospect of Human Clinical Translation. Stem Cells Int 2020; 2020:8837654. [PMID: 33953753 PMCID: PMC8063852 DOI: 10.1155/2020/8837654] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/19/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/progenitor cells (MSCs) are key players in regenerative medicine, relying principally on their differentiation/regeneration potential, immunomodulatory properties, paracrine effects, and potent homing ability with minimal if any ethical concerns. Even though multiple preclinical and clinical studies have demonstrated remarkable properties for MSCs, the clinical applicability of MSC-based therapies is still questionable. Several challenges exist that critically hinder a successful clinical translation of MSC-based therapies, including but not limited to heterogeneity of their populations, variability in their quality and quantity, donor-related factors, discrepancies in protocols for isolation, in vitro expansion and premodification, and variability in methods of cell delivery, dosing, and cell homing. Alterations of MSC viability, proliferation, properties, and/or function are also affected by various drugs and chemicals. Moreover, significant safety concerns exist due to possible teratogenic/neoplastic potential and transmission of infectious diseases. Through the current review, we aim to highlight the major challenges facing MSCs' human clinical translation and shed light on the undergoing strategies to overcome them.
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Desai S, Jayasuriya CT. Implementation of Endogenous and Exogenous Mesenchymal Progenitor Cells for Skeletal Tissue Regeneration and Repair. Bioengineering (Basel) 2020; 7:E86. [PMID: 32759659 PMCID: PMC7552784 DOI: 10.3390/bioengineering7030086] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 07/25/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023] Open
Abstract
Harnessing adult mesenchymal stem/progenitor cells to stimulate skeletal tissue repair is a strategy that is being actively investigated. While scientists continue to develop creative and thoughtful ways to utilize these cells for tissue repair, the vast majority of these methodologies can ultimately be categorized into two main approaches: (1) Facilitating the recruitment of endogenous host cells to the injury site; and (2) physically administering into the injury site cells themselves, exogenously, either by autologous or allogeneic implantation. The aim of this paper is to comprehensively review recent key literature on the use of these two approaches in stimulating healing and repair of different skeletal tissues. As expected, each of the two strategies have their own advantages and limitations (which we describe), especially when considering the diverse microenvironments of different skeletal tissues like bone, tendon/ligament, and cartilage/fibrocartilage. This paper also discusses stem/progenitor cells commonly used for repairing different skeletal tissues, and it lists ongoing clinical trials that have risen from the implementation of these cells and strategies. Lastly, we discuss our own thoughts on where the field is headed in the near future.
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Affiliation(s)
| | - Chathuraka T. Jayasuriya
- Department of Orthopaedics, Warren Alpert Medical School of Brown University and the Rhode Island Hospital, Providence, RI 02903, USA;
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Arjmand B, Sarvari M, Alavi-Moghadam S, Payab M, Goodarzi P, Gilany K, Mehrdad N, Larijani B. Prospect of Stem Cell Therapy and Regenerative Medicine in Osteoporosis. Front Endocrinol (Lausanne) 2020; 11:430. [PMID: 32719657 PMCID: PMC7347755 DOI: 10.3389/fendo.2020.00430] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 06/01/2020] [Indexed: 12/13/2022] Open
Abstract
The field of cell therapy and regenerative medicine can hold the promise of restoring normal tissues structure and function. Additionally, the main targets of stem cell-based therapies are chronic diseases and lifelong disabilities without definite cures such as osteoporosis. Osteoporosis as one of the important causes of morbidity in older men and post-menopausal women is characterized by reduced bone quantity or skeletal tissue atrophy that leads to an increased risk of osteoporotic fractures. The common therapeutic methods for osteoporosis only can prevent the loss of bone mass and recover the bone partially. Nevertheless, stem cell-based therapy is considered as a new approach to regenerate the bone tissue. Herein, mesenchymal stem cells as pivotal candidates for regenerative medicine purposes especially bone regeneration are the most common type of cells with anti-inflammatory, immune-privileged potential, and less ethical concerns than other types of stem cells which are investigated in osteoporosis. Based on several findings, the mesenchymal stem cells effectiveness near to a great extent depends on their secretory function. Indeed, they can be involved in the establishment of normal bone remodeling via initiation of specific molecular signaling pathways. Accordingly, the aim herein was to review the effects of stem cell-based therapies in osteoporosis.
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Affiliation(s)
- Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Sarvari
- Metabolomics and Genomics Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepideh Alavi-Moghadam
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moloud Payab
- Obesity and Eating Habits Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Goodarzi
- Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Kambiz Gilany
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
- Integrative Oncology Department, Breast Cancer Research Center, Motamed Cancer Institute, Academic Center for Education, Culture and Research (ACER), Tehran, Iran
- Reproductive Immunology Research Center, Avicenna Research Institute, Academic Center for Education, Culture and Research (ACER), Tehran, Iran
| | - Neda Mehrdad
- Elderly Health Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
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Čamernik K, Mihelič A, Mihalič R, Haring G, Herman S, Marolt Presen D, Janež A, Trebše R, Marc J, Zupan J. Comprehensive analysis of skeletal muscle- and bone-derived mesenchymal stem/stromal cells in patients with osteoarthritis and femoral neck fracture. Stem Cell Res Ther 2020; 11:146. [PMID: 32245507 PMCID: PMC7118858 DOI: 10.1186/s13287-020-01657-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 02/24/2020] [Accepted: 03/18/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Mesenchymal stem/stromal cells (MSCs) can replenish the aged cells of the musculoskeletal system in adult life. Stem cell exhaustion and decrease in their regenerative potential have been suggested to be hallmarks of aging. Here, we investigated whether muscle- and bone-derived MSCs of patients with osteoarthritis and osteoporosis are affected by this exhaustion, compared to healthy donors. METHODS Patients with primary osteoarthritis, femoral neck fractures due to osteoporosis, and healthy donors (controls) were included. MSCs were isolated from the skeletal muscle and subchondral bone from each patient and compared using ex vivo and in vitro analyses, including immunophenotyping, colony-forming unit fibroblast assays, growth kinetics, cell senescence, multilineage potential, and MSC marker gene expression profiling. RESULTS Freshly isolated cells from muscle from patients with osteoarthritis showed a lower proportion of CD45/CD19/CD14/CD34-negative cells compared to patients with osteoporosis and healthy donors. Freshly isolated muscle cells from patients with osteoarthritis and osteoporosis also showed higher clonogenicity compared to healthy donors. MSCs from both tissues of osteoarthritis patients showed significantly reduced osteogenesis and MSCs from the bone also reduced adipogenesis. Chondrogenic pellet diameter was reduced in bone-derived MSCs from both patient groups compared to healthy donors. A significant positive correlation was observed between adipogenesis and CD271 expression in muscle-derived MSCs. CD73 was significantly lower in bone-derived MSCs from osteoarthritis patients, compared to osteoporosis patients. Gene expression profiling showed significantly lower expression of MSC marker gene leptin receptor, LEPR, previously identified as the major source of the bone and adipocytes in the adult bone marrow, in bone-derived MSCs from patients with osteoarthritis in comparison with osteoporotic patients and healthy donors. CONCLUSIONS Our results show deficient ex vivo and in vitro properties of both skeletal muscle- and bone-derived MSCs in osteoarthritis and osteoporosis patients, compared to healthy donors. In bone-derived MSCs from patients with osteoarthritis, we also identified a lower expression of the leptin receptor, a marker of MSCs that present a major source of MSCs in the adult bone marrow. This suggests that exhaustion of skeletal muscle- and bone-derived MSCs is a hallmark of osteoarthritis and osteoporosis, which defines the need for further clinical trials of stem cell transplantation in these patients.
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Affiliation(s)
- Klemen Čamernik
- University of Ljubljana, Faculty of Pharmacy, Chair of Clinical Biochemistry, Askerceva 7, 1000, Ljubljana, Slovenia
| | - Anže Mihelič
- Valdoltra Orthopaedic Hospital, Jadranska 31, SI-6280, Ankaran, Slovenia
| | - Rene Mihalič
- Valdoltra Orthopaedic Hospital, Jadranska 31, SI-6280, Ankaran, Slovenia
| | - Gregor Haring
- University of Ljubljana, Faculty of Medicine, Institute of Forensic Medicine, Korytkova 2, 1000, Ljubljana, Slovenia
| | - Simon Herman
- Clinical Department of Traumatology, University Medical Centre, Zaloska cesta 7, 1000, Ljubljana, Slovenia
| | - Darja Marolt Presen
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Austrian Cluster for Tissue Regeneration, Donaueschingenstrasse 13, A-1200, Vienna, Austria
| | - Andrej Janež
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre, Zaloska cesta 2, 1000, Ljubljana, Slovenia
| | - Rihard Trebše
- Valdoltra Orthopaedic Hospital, Jadranska 31, SI-6280, Ankaran, Slovenia
| | - Janja Marc
- University of Ljubljana, Faculty of Pharmacy, Chair of Clinical Biochemistry, Askerceva 7, 1000, Ljubljana, Slovenia
| | - Janja Zupan
- University of Ljubljana, Faculty of Pharmacy, Chair of Clinical Biochemistry, Askerceva 7, 1000, Ljubljana, Slovenia.
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McInnis KC, Chen ET, Finnoff JT, Roh EY, Borg Stein J. Orthobiologics for the Hip Region: A Narrative Review. PM R 2020; 12:1045-1054. [PMID: 31953917 DOI: 10.1002/pmrj.12327] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 01/13/2020] [Indexed: 12/19/2022]
Abstract
Management of hip region disorders is challenging. Orthobiologic treatments including platelet rich plasma (PRP), mesenchymal stem cells, and amniotic injectables have gained popularity as promising treatments despite a lack of robust evidence for their effectiveness. We review rationale and current evidence for orthobiologics for three common hip region conditions: hip osteoarthritis, gluteal tendinopathy, and proximal hamstring tendinopathy. Overall, the current state of evidence is extremely limited for orthobiologic treatments and is predominantly relevant to PRP injections. There is currently a lack of data to support the use of mesenchymal stem cells or amniotic injectables in these conditions of the hip.
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Affiliation(s)
- Kelly C McInnis
- Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA
| | - Eric T Chen
- Department of Rehabilitation Medicine, University of Washington, Seattle, WA
| | - Jonathan T Finnoff
- Department of Physical Medicine and Rehabilitation, Mayo Clinic College of Medicine and Science, Rochester, MN
| | - Eugene Y Roh
- Department of Orthopedic Surgery, Physical Medicine and Rehabilitation, Stanford University, Redwood City, CA
| | - Joanne Borg Stein
- Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA
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Role of nanofibers on MSCs fate: Influence of fiber morphologies, compositions and external stimuli. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 107:110218. [DOI: 10.1016/j.msec.2019.110218] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 09/04/2019] [Accepted: 09/16/2019] [Indexed: 01/09/2023]
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Govarthanan K, Vidyasekar P, Gupta PK, Lenka N, Verma RS. Glycogen synthase kinase 3β inhibitor- CHIR 99021 augments the differentiation potential of mesenchymal stem cells. Cytotherapy 2020; 22:91-105. [PMID: 31980369 DOI: 10.1016/j.jcyt.2019.12.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 11/22/2019] [Accepted: 12/11/2019] [Indexed: 12/23/2022]
Abstract
AIM Mesenchymal stem cells (MSCs) are immunomodulatory, non-teratogenic and multipotent alternatives to embryonic or induced pluripotent stem cells (ESCs or iPSCs). However, the potency of MSCs is not equivalent to the pluripotency of ESCs or iPSCs. We used CHIR 99021 to improve current protocols and methods of differentiation for the enhanced transdifferentiation potency of MSCs. MAIN METHODS We used Flurescence activated cell sorter (FACS) for MSC immunophenotyping and biochemical assay for demonstrating the trilineage potential of MSCs. We used real-time polymerase chain reaction, immunocytochemistry and Western blotting assay for analyzing the expression of lineage-specific markers. KEY FINDINGS CHIR 99021 treatment of MSCs resulted in enhanced transdifferentiation into neurological, hepatogenic and cardiomyocyte lineages with standardized protocols of differentiation. CHIR 99021-treated MSCs showed increased nuclear localization of β-catenin. These MSCs showed a significantly increased deposition of active histone marks (H3K4Me3, H3K36Me3), whereas no change was observed in repressive marks (H3K9Me3, H3K27Me3). Differential methylation profiling showed demethylation of the transcription factor OCT4 promoter region with subsequent analysis revealing increased gene expression and protein content. The HLA-DR antigen was absent in CHIR 99021-treated MSCs and their differentiated cell types, indicating their immune-privileged status. Karyotyping analysis showed that CHIR 99021-treated MSCs were genomically stable. Teratoma analysis of nude mice injected with CHIR 99021-treated MSCs showed the increased presence of cell types of mesodermal origin at the site of injection. SIGNIFICANCE MSCs pretreated with CHIR 99021 can be potent, abundant alternative sources of stem cells with enhanced differentiation capabilities that are well suited to cell-based regenerative therapy.
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Affiliation(s)
- Kavitha Govarthanan
- Stem Cell and Molecular Biology Lab, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamilnadu, India
| | - Prasanna Vidyasekar
- Stem Cell and Molecular Biology Lab, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamilnadu, India
| | - Piyush Kumar Gupta
- Stem Cell and Molecular Biology Lab, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamilnadu, India
| | - Nibedita Lenka
- National Centre for Cell Science, Pune, Maharashtra, India
| | - Rama Shanker Verma
- Stem Cell and Molecular Biology Lab, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamilnadu, India.
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Xue E, Milano F. Are we underutilizing bone marrow and cord blood? Review of their role and potential in the era of cellular therapies. F1000Res 2020; 9. [PMID: 31984133 PMCID: PMC6970216 DOI: 10.12688/f1000research.20605.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/07/2020] [Indexed: 12/12/2022] Open
Abstract
Since the first hematopoietic stem cell transplant, over a million transplants have been performed worldwide. In the last decade, the transplant field has witnessed a progressive decline in bone marrow and cord blood utilization and a parallel increase in peripheral blood as a source of stem cells. Herein, we review the use of bone marrow and cord blood in the hematopoietic stem cell transplant setting, and we describe the recent advances made in different medical fields using cells derived from cord blood and bone marrow.
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Affiliation(s)
- Elisabetta Xue
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA, 98109, USA.,Hematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute IRCCS, Milan, Italy
| | - Filippo Milano
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, Seattle, WA, 98109, USA
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Xing J, Lu Y, Cui Y, Zhu X, Luo F, Xie Z, Wu X, Deng M, Xu J, Hou T. A Standardized and Quality-Controllable Protocol of Constructing Individual Tissue-Engineered Grafts Applicable to Treating Large Bone Defects. Tissue Eng Part C Methods 2020; 25:137-147. [PMID: 30734646 DOI: 10.1089/ten.tec.2018.0323] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Patient-specific individual tissue-engineered bones (iTEBs) have been recognized as a promising strategy for treating large bone defects. However, current construction protocols of iTEBs vary between lots and lack standardization and quality control, hampering further research and application. This study was aimed to detail a standardized constructing protocol for iTEBs, which can be used for both clinical and experimental purposes. The procedure was designed and described as follows: scaffold preparation, cell isolation and culture, and fabrication of iTEBs. Manipulation and caution points in each section were detailed. A series of scales on the quality control and safety monitoring was developed. The effectiveness and safety of iTEBs were evaluated. Eventually, the preparing portion, from cell culture to scaffold treatment, usually required 21 days. Generally, the fabrication section took 5 days. The main advantage of this protocol was that each step was standardized and quality controlling and safety monitoring were performed throughout the process to ensure the homogeneity, reliability, and safety. The resulting iTEBs were effective and applicable to both clinical and experimental purposes. Thus, we have established a refined and standardized protocol detailing the construction process of patient-specific iTEBs that comply with strict quality control and safety criteria. This protocol is relatively easy for graduate students or staff working in the field of bone tissue engineering to implement.
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Affiliation(s)
- Junchao Xing
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Department of Orthopedics, Southwest Hospital, the Third Military Medical University, Chongqing, China.,2 Center of Regenerative and Reconstructive Engineering Technology in Chongqing City, Chongqing, China.,3 Tissue Engineering Laboratory of Chongqing City, Chongqing, China
| | | | - Yigong Cui
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Department of Orthopedics, Southwest Hospital, the Third Military Medical University, Chongqing, China.,2 Center of Regenerative and Reconstructive Engineering Technology in Chongqing City, Chongqing, China.,3 Tissue Engineering Laboratory of Chongqing City, Chongqing, China
| | - Xiaobo Zhu
- 4 Outpatient Department of 31668 Unit of PLA, Xining, China
| | - Fei Luo
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Department of Orthopedics, Southwest Hospital, the Third Military Medical University, Chongqing, China.,2 Center of Regenerative and Reconstructive Engineering Technology in Chongqing City, Chongqing, China.,3 Tissue Engineering Laboratory of Chongqing City, Chongqing, China
| | - Zhao Xie
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Department of Orthopedics, Southwest Hospital, the Third Military Medical University, Chongqing, China.,2 Center of Regenerative and Reconstructive Engineering Technology in Chongqing City, Chongqing, China.,3 Tissue Engineering Laboratory of Chongqing City, Chongqing, China
| | - Xuehui Wu
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Department of Orthopedics, Southwest Hospital, the Third Military Medical University, Chongqing, China.,2 Center of Regenerative and Reconstructive Engineering Technology in Chongqing City, Chongqing, China.,3 Tissue Engineering Laboratory of Chongqing City, Chongqing, China
| | - Moyuan Deng
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Department of Orthopedics, Southwest Hospital, the Third Military Medical University, Chongqing, China.,2 Center of Regenerative and Reconstructive Engineering Technology in Chongqing City, Chongqing, China.,3 Tissue Engineering Laboratory of Chongqing City, Chongqing, China
| | - Jianzhong Xu
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Department of Orthopedics, Southwest Hospital, the Third Military Medical University, Chongqing, China.,2 Center of Regenerative and Reconstructive Engineering Technology in Chongqing City, Chongqing, China.,3 Tissue Engineering Laboratory of Chongqing City, Chongqing, China
| | - Tianyong Hou
- 1 National & Regional United Engineering Laboratory of Tissue Engineering, Department of Orthopedics, Southwest Hospital, the Third Military Medical University, Chongqing, China.,2 Center of Regenerative and Reconstructive Engineering Technology in Chongqing City, Chongqing, China.,3 Tissue Engineering Laboratory of Chongqing City, Chongqing, China
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Bone Marrow-Derived Mesenchymal Stromal Cells: A Novel Target to Optimize Hematopoietic Stem Cell Transplantation Protocols in Hematological Malignancies and Rare Genetic Disorders. J Clin Med 2019; 9:jcm9010002. [PMID: 31861268 PMCID: PMC7019991 DOI: 10.3390/jcm9010002] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 12/11/2019] [Accepted: 12/12/2019] [Indexed: 12/13/2022] Open
Abstract
: Mesenchymal stromal cells (MSCs) are crucial elements in the bone marrow (BM) niche where they provide physical support and secrete soluble factors to control and maintain hematopoietic stem progenitor cells (HSPCs). Given their role in the BM niche and HSPC support, MSCs have been employed in the clinical setting to expand ex-vivo HSPCs, as well as to facilitate HSPC engraftment in vivo. Specific alterations in the mesenchymal compartment have been described in hematological malignancies, as well as in rare genetic disorders, diseases that are amenable to allogeneic hematopoietic stem cell transplantation (HSCT), and ex-vivo HSPC-gene therapy (HSC-GT). Dissecting the in vivo function of human MSCs and studying their biological and functional properties in these diseases is a critical requirement to optimize transplantation outcomes. In this review, the role of MSCs in the orchestration of the BM niche will be revised, and alterations in the mesenchymal compartment in specific disorders will be discussed, focusing on the need to correct and restore a proper microenvironment to ameliorate transplantation procedures, and more in general disease outcomes.
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Pirosa A, Clark KL, Tan J, Yu S, Yang Y, Tuan RS, Alexander PG. Modeling appendicular skeletal cartilage development with modified high-density micromass cultures of adult human bone marrow-derived mesenchymal progenitor cells. Stem Cell Res Ther 2019; 10:388. [PMID: 31842986 PMCID: PMC6916440 DOI: 10.1186/s13287-019-1505-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 11/15/2019] [Accepted: 11/20/2019] [Indexed: 01/17/2023] Open
Abstract
Background Animal cell-based systems have been critical tools in understanding tissue development and physiology, but they are less successful in more practical tasks, such as predicting human toxicity to pharmacological or environmental factors, in which the congruence between in vitro and clinical outcomes lies on average between 50 and 60%. Emblematic of this problem is the high-density micromass culture of embryonic limb bud mesenchymal cells, derived from chick, mouse, or rat. While estimated predictive value of this model system in toxicological studies is relatively high, important failures prevent its use by international regulatory agencies for toxicity testing and policy development. A likely underlying reason for the poor predictive capacity of animal-based culture models is the small but significant physiological differences between species. This deficiency has inspired investigators to develop more organotypic, 3-dimensional culture system using human cells to model normal tissue development and physiology and assess pharmacological and environmental toxicity. Methods We have developed a modified, miniaturized micromass culture model using adult human bone marrow-derived mesenchymal progenitor cells (hBM-MPCs) that is amenable to moderate throughput and high content analysis to study chondrogenesis. The number of cells per culture was reduced, and a methacrylated gelatin (gelMA) overlay was incorporated to normalize the morphology of the cultures. Results These modified human cell-based micromass cultures demonstrated robust chondrogenesis, indicated by increased Alcian blue staining and immunodetectable production of collagen type II and aggrecan, and stage-specific chondrogenic gene expression. In addition, in cultures of hBM-MPCs transduced with a lentiviral collagen type II promoter-driven GFP reporter construct, levels of GFP reporter activity correlated well with changes in endogenous collagen type II transcript levels, indicating the feasibility of non-invasive monitoring of chondrogenesis. Conclusions The modified hBM-MPC micromass culture system described here represents a reproducible and controlled model for analyzing mechanisms of human skeletal development that may later be applied to pharmacological and environmental toxicity studies.
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Affiliation(s)
- Alessandro Pirosa
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219, USA
| | - Karen L Clark
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219, USA
| | - Jian Tan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219, USA
| | - Shuting Yu
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219, USA
| | - Yuanheng Yang
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219, USA
| | - Rocky S Tuan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219, USA.,Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Peter G Alexander
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219, USA.
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Dragoo JL, Meadows MC. The use of biologics for the elbow: a critical analysis review. J Shoulder Elbow Surg 2019; 28:2053-2060. [PMID: 31585783 DOI: 10.1016/j.jse.2019.07.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 07/28/2019] [Indexed: 02/01/2023]
Abstract
There is significant interest in biologic treatment options to improve the healing environment and more rapidly decrease symptoms in many conditions around the elbow. Despite fairly widespread use of biologic agents such as platelet-rich plasma (PRP) in the elbow, there is a lack of clear evidence in the literature to support its use. The potential impact of these biologic agents must be evaluated with evidence from high-quality studies, particularly considering the high financial burden these treatments often impose on patients. The aim of this review is to provide an evidence-based summary of the biologic augmentation options available for use by the physician treating painful conditions of the elbow and to identify areas where further research is warranted.
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Affiliation(s)
- Jason L Dragoo
- Department of Orthopaedic Surgery, University of Colorado, Denver, CO, USA.
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Abazari MF, Nasiri N, Nejati F, Zare Karizi S, Amini Faskhodi M, Saburi E, Aghapur N, Mahdavi MR, Ardeshirylajimi A, Enderami SE, Soleimanifar F. Comparison of human‐induced pluripotent stem cells and mesenchymal stem cell differentiation potential to insulin producing cells in 2D and 3D culture systems in vitro. J Cell Physiol 2019; 235:4239-4246. [DOI: 10.1002/jcp.29298] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 09/30/2019] [Indexed: 12/31/2022]
Affiliation(s)
- Mohammad Foad Abazari
- Research Center for Clinical Virology Tehran University of Medical Sciences Tehran Iran
| | - Navid Nasiri
- Department of Biology, Central Tehran Branch Islamic Azad University Tehran Iran
| | - Fatemeh Nejati
- Department of Biology, Central Tehran Branch Islamic Azad University Tehran Iran
| | - Shohreh Zare Karizi
- Department of biology, Varamin Pishva branch Islamic Azad University Pishva Varamin Iran
| | | | - Ehsan Saburi
- Medical Genetics and Molecular Medicine Department, School of Medicine Mashhad University of Medical Sciences Mashhad Iran
| | - Nasrin Aghapur
- Department of Biotechnology, Faculty of Science University of Tehran Tehran Iran
| | | | | | - Seyed Ehsan Enderami
- Diabetes Research Center Mazandaran University of Medical Sciences Sari Iran
- Immunogenetics Research Center, Department of Medical Biotechnology Mazandaran University of Medical Sciences Sari Iran
| | - Fatemeh Soleimanifar
- Dietary Supplements and Probiotic Research Center Alborz University of Medical Sciences Karaj Iran
- Department of Medical Biotechnology, School of Medicine Alborz University of Medical Sciences Karaj Iran
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Gaul F, Bugbee WD, Hoenecke HR, D’Lima DD. A Review of Commercially Available Point-of-Care Devices to Concentrate Bone Marrow for the Treatment of Osteoarthritis and Focal Cartilage Lesions. Cartilage 2019; 10:387-394. [PMID: 29652173 PMCID: PMC6755874 DOI: 10.1177/1947603518768080] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Mesenchymal stem cells (MSCs) are a promising cell-based therapy treatment option for several orthopedic indications. Because culture expansion of MSC is time and cost intensive, a bedside concentration of bone marrow (BM) aspirate is used as an alternative. Many commercial systems are available but the available literature and knowledge regarding these systems is limited. We compared different point-of-care devices that concentrate BM (BMC) by focusing on technical features and quality parameters to help surgeons make informed decisions while selecting the appropriate device. METHODS We compared published data on the BMC devices of Arteriocyte, Arthrex, Celling Biosciences, EmCyte, Exactech, ISTO Tech, Harvest Tech/Terumo BCT, and Zimmer/BIOMET regarding technical features (centrifugation speed/time, input/output volume, kit components, type of aspiration syringes, filter usage) and quality parameters of their final BMC product (hematocrit, concentration of platelets and total nucleated cells, concentration of MSC and connective tissue progenitor cells). RESULTS The systems differ significantly in their technical features and centrifugation parameters. Only the fully automated systems use universal kits, which allow processing different volumes of BM. Only the Arthrex system allows selection of final hematocrit. There was no standardized reporting method to describe biologic potency. CONCLUSIONS Based on the data obtained in this review, recommending a single device is not possible because the reported data could not be compared between devices. A standardized reporting method is needed for valid comparisons. Furthermore, clinical outcomes are required to establish the true efficacy of these systems. We are conducting additional studies for more careful comparison among the devices.
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Affiliation(s)
- Florian Gaul
- Shiley Center for Orthopaedic Research and Education at Scripps Clinic, La Jolla, CA, USA,Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA,Department of Orthopaedic, Trauma and Plastic Surgery, University Hospital Leipzig, German
| | | | | | - Darryl D. D’Lima
- Shiley Center for Orthopaedic Research and Education at Scripps Clinic, La Jolla, CA, USA,Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA,Darryl D. D’Lima, Shiley Center for Orthopaedic Research and Education at Scripps Clinic, 10550 North Torrey Pine Road, MEM-116, La Jolla, CA 92037, USA.
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Mastrolia I, Foppiani EM, Murgia A, Candini O, Samarelli AV, Grisendi G, Veronesi E, Horwitz EM, Dominici M. Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review. Stem Cells Transl Med 2019; 8:1135-1148. [PMID: 31313507 PMCID: PMC6811694 DOI: 10.1002/sctm.19-0044] [Citation(s) in RCA: 203] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 06/17/2019] [Indexed: 02/06/2023] Open
Abstract
Identified 50 years ago, mesenchymal stromal/stem cells (MSCs) immediately generated a substantial interest among the scientific community because of their differentiation plasticity and hematopoietic supportive function. Early investigations provided evidence of a relatively low engraftment rate and a transient benefit for challenging congenital and acquired diseases. The reasons for these poor therapeutic benefits forced the entire field to reconsider MSC mechanisms of action together with their ex vivo manipulation procedures. This phase resulted in advances in MSCs processing and the hypothesis that MSC‐tissue supportive functions may be prevailing their differentiation plasticity, broadening the spectrum of MSCs therapeutic potential far beyond their lineage‐restricted commitments. Consequently, an increasing number of studies have been conducted for a variety of clinical indications, revealing additional challenges and suggesting that MSCs are still lagging behind for a solid clinical translation. For this reason, our aim was to dissect the current challenges in the development of still promising cell types that, after more than half a century, still need to reach their maturity. stem cells translational medicine2019;8:1135–1148
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Affiliation(s)
- Ilenia Mastrolia
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Elisabetta Manuela Foppiani
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA
| | - Alba Murgia
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | | | - Anna Valeria Samarelli
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy
| | - Elena Veronesi
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.,Technopole of Mirandola TPM, Mirandola, Modena, Italy
| | - Edwin M Horwitz
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta, Georgia, USA
| | - Massimo Dominici
- Laboratory of Cellular Therapy, Program of Cell Therapy and Immuno-Oncology, Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.,Rigenerand srl, Medolla, Modena, Italy.,Technopole of Mirandola TPM, Mirandola, Modena, Italy
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Stem cells in Osteoporosis: From Biology to New Therapeutic Approaches. Stem Cells Int 2019; 2019:1730978. [PMID: 31281368 PMCID: PMC6589256 DOI: 10.1155/2019/1730978] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 04/21/2019] [Accepted: 04/23/2019] [Indexed: 12/11/2022] Open
Abstract
Osteoporosis is a systemic disease that affects the skeleton, causing reduction of bone density and mass, resulting in destruction of bone microstructure and increased risk of bone fractures. Since osteoporosis is a disease affecting the elderly and the aging of the world's population is constantly increasing, it is expected that the incidence of osteoporosis and its financial burden on the insurance systems will increase continuously and there is a need for more understanding this condition in order to prevent and/or treat it. At present, available drug therapy for osteoporosis primarily targets the inhibition of bone resorption and agents that promote bone mineralization, designed to slow disease progression. Safe and predictable pharmaceutical means to increase bone formation have been elusive. Stem cell therapy of osteoporosis, as a therapeutic strategy, offers the promise of an increase in osteoblast differentiation and thus reversing the shift towards bone resorption in osteoporosis. This review is focused on the current views regarding the implication of the stem cells in the cellular and physiologic mechanisms of osteoporosis and discusses data obtained from stem cell-based therapies of osteoporosis in experimental animal models and the possibility of their future application in clinical trials.
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