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Otsuka Y, Adili A, Momoeda M, Negishi Y, Kaneko H, Yoshinaga C, Kenzaki Y, Negishi-Koga T, Ishijima M, Okada Y. Involvement of Heat Shock Protein 47 in Osteophyte Formation of Knee Joint Osteoarthritis. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00104-X. [PMID: 40204189 DOI: 10.1016/j.ajpath.2025.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 02/19/2025] [Accepted: 03/11/2025] [Indexed: 04/11/2025]
Abstract
Osteophytes contribute to the development and progression of knee osteoarthritis (OA). Although transforming growth factor-β (TGF-β) and bone morphogenic protein-2 (BMP2) are known to induce osteophytes, regulators of osteophyte formation remain elusive. This study aimed to search for molecules that modulate osteophytosis in a mouse knee OA model. Proteomic analysis, followed by immunohistochemistry of osteophyte and articular cartilage, identified heat shock protein 47 (HSP47), a molecular chaperone for procollagens, as a molecule selectively overexpressed by osteophyte fibrocartilaginous cells. The treatment of TGF-β3 and BMP2 to a three-dimensional pellet culture of mouse mesenchymal stem cells caused their differentiation into osteophyte-like cells accompanied with the up-regulation of HSP47. The pellet sizes of stimulated three-dimensional-cultured mesenchymal stem cells were significantly reduced by knockdown of HSP47 or treatment with AK778 (HSP47 inhibitor), because of increased apoptosis. Furthermore, intra-articular AK778 injections suppressed osteophyte formation in a mouse OA model. Importantly, the studies with human samples demonstrated HSP47 overexpression by osteophyte fibrocartilaginous cells in human OA knee joints. Similarly, the overexpression of HSP47 was observed in the TGF-β3- and BMP2-treated human osteophytic cell spheroids as well as the size reduction of spheroids by AK778 treatment. These findings highlight the promoting function of HSP47 in osteophyte formation in OA knee joints and suggest that therapeutic interventions targeting HSP47 may be of clinical value.
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Affiliation(s)
- Yuta Otsuka
- Department of Pathophysiology for Locomotive Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Arepati Adili
- Department of Pathophysiology for Locomotive Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan; Sportology Center, Juntendo University, Tokyo, Japan
| | - Masahiro Momoeda
- Department of Pathophysiology for Locomotive Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Negishi
- Department of Pathophysiology for Locomotive Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Haruka Kaneko
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Chiho Yoshinaga
- Department of Pathophysiology for Locomotive Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuka Kenzaki
- Department of Pathophysiology for Locomotive Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takako Negishi-Koga
- Department of Pathophysiology for Locomotive Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Community Medicine and Research for Bone and Joint Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Muneaki Ishijima
- Department of Pathophysiology for Locomotive Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan; Sportology Center, Juntendo University, Tokyo, Japan; Department of Community Medicine and Research for Bone and Joint Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasunori Okada
- Department of Pathophysiology for Locomotive Diseases, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo, Japan.
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Zhao Z, Wang P, Li Z, Wei X, Li S, Lu X, Dai S, Huang B, Man Z, Li W. Targeted lipid nanoparticles distributed in hydrogel treat osteoarthritis by modulating cholesterol metabolism and promoting endogenous cartilage regeneration. J Nanobiotechnology 2024; 22:786. [PMID: 39707367 DOI: 10.1186/s12951-024-02965-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Accepted: 10/31/2024] [Indexed: 12/23/2024] Open
Abstract
Osteoarthritis (OA) is the most common disease in aging joints and has characteristics of cartilage destruction and inflammation. It is currently considered a metabolic disease, and the CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes plays a crucial catabolic regulatory role in its pathogenesis. Targeting of this axis in chondrocytes may provide a therapeutic approach for OA treatment. Here, in this study, we propose to use a combination of stem cell-recruiting hydrogels and lipid nanoparticles (LNPs) that modulate cholesterol metabolism to jointly promote a regenerative microenvironment. Specifically, we first developed an injectable, bioactive hydrogel composed of self-assembling peptide nanofibers that recruits endogenous synovial stem cells (SMSCs) and promotes their chondrogenic differentiation. At the same time, LNPs that regulate cholesterol metabolism are incorporated into the hydrogel and slowly released, thereby improving the inflammatory environment of OA. Enhancements were noted in the inflammatory conditions associated with OA, alongside the successful attraction of mesenchymal stem cells (MSCs) from the synovial membrane. These cells were then observed to differentiate into chondrocytes, contributing to effective cartilage restoration and chondrocyte regeneration, thereby offering a promising approach for OA treatment. In summary, this approach provides a feasible siRNA-based therapeutic option, offering a potential nonsurgical solution for treatment of OA.
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Affiliation(s)
- Zhibo Zhao
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Peng Wang
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Ziyang Li
- Department of Sports Medicine & Orthopedic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, People's Republic of China
| | - Xingchen Wei
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Shishuo Li
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China
| | - Xiaoqing Lu
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China
| | - Shimin Dai
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China
| | - Benzhao Huang
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China
| | - Zhentao Man
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, People's Republic of China.
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.
- College of Sports Medicine and Rehabilitation, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, People's Republic of China.
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250062, People's Republic of China.
| | - Wei Li
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, People's Republic of China.
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People's Republic of China.
- College of Sports Medicine and Rehabilitation, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, People's Republic of China.
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Poudel SB, Ruff RR, Yildirim G, Miller RA, Harrison DE, Strong R, Kirsch T, Yakar S. Development of primary osteoarthritis during aging in genetically diverse UM-HET3 mice. Arthritis Res Ther 2024; 26:118. [PMID: 38851726 PMCID: PMC11161968 DOI: 10.1186/s13075-024-03349-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 05/27/2024] [Indexed: 06/10/2024] Open
Abstract
BACKGROUND Primary osteoarthritis (OA) occurs without identifiable underlying causes such as previous injuries or specific medical conditions. Age is a major contributing factor to OA, and as one ages, various joint tissues undergo gradual change, including degeneration of the articular cartilage, alterations in subchondral bone (SCB) morphology, and inflammation of the synovium. METHODS We investigated the prevalence of primary OA in aged, genetically diverse UM-HET3 mice. Articular cartilage (AC) integrity and SCB morphology were assessed in 182 knee joints of 22-25 months old mice using the Osteoarthritis Research Society International (OARSI) scoring system and micro-CT, respectively. Additionally, we explored the effects of methylene blue (MB) and mitoquinone (MitoQ), two agents that affect mitochondrial function, on the prevalence and progression of OA during aging. RESULTS Aged UM-HET3 mice showed a high prevalence of primary OA in both sexes. Significant positive correlations were found between cumulative AC (cAC) scores and synovitis in both sexes, and osteophyte formation in female mice. Ectopic chondrogenesis did not show significant correlations with cAC scores. Significant direct correlations were found between AC scores and inflammatory markers in chondrocytes, including matrix metalloproteinase-13, inducible nitric oxide synthase, and the NLR family pyrin domain containing-3 inflammasome in both sexes, indicating a link between OA severity and inflammation. Additionally, markers of cell cycle arrest, such as p16 and β-galactosidase, also correlated with AC scores. In male mice, no significant correlations were found between SCB morphology traits and cAC scores, while in female mice, significant correlations were found between cAC scores and tibial SCB plate bone mineral density. Notably, MB and MitoQ treatments influenced the disease's progression in a sex-specific manner. MB treatment significantly reduced cAC scores at the medial knee joint, while MitoQ treatment reduced cAC scores, but these did not reach significance. CONCLUSIONS Our study provides comprehensive insights into the prevalence and progression of primary OA in aged UM-HET3 mice, highlighting the sex-specific effects of MB and MitoQ treatments. The correlations between AC scores and various pathological factors underscore the multifaceted nature of OA and its association with inflammation and subchondral bone changes.
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Affiliation(s)
- Sher Bahadur Poudel
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, 345 East 24th Street, New York, NY, 10010-4086, USA
| | - Ryan R Ruff
- David B. Kriser Dental Center, Biostatistics Core, Department of Epidemiology and Health Promotion, New York University College of Dentistry, New York, NY, 10010-4086, USA
| | - Gozde Yildirim
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, 345 East 24th Street, New York, NY, 10010-4086, USA
| | - Richard A Miller
- Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, 48105, USA
| | | | - Randy Strong
- Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA
- Barshop Institute for Longevity and Aging Studies and Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, 78229, USA
| | - Thorsten Kirsch
- Department of Orthopaedic Surgery, NYU Grossman School of Medicine, New York, NY, 10100, USA
- Department of Biomedical Engineering, NYU Tandon School of Engineering, New York, NY, 10010, USA
| | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, 345 East 24th Street, New York, NY, 10010-4086, USA.
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Poudel SB, Ruff RR, Yildirim G, Miller RA, Harrison DE, Strong R, Kirsch T, Yakar S. Development of primary osteoarthritis during aging in genetically diverse UM-HET3 mice. RESEARCH SQUARE 2024:rs.3.rs-3858256. [PMID: 38343826 PMCID: PMC10854287 DOI: 10.21203/rs.3.rs-3858256/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/03/2024]
Abstract
Background Primary osteoarthritis (OA) occurs without identifiable underlying causes such as previous injuries or specific medical conditions. Age is a major contributing factor to OA, and as one ages, various joint tissues undergo gradual change, including degeneration of the articular cartilage, alterations in subchondral bone (SCB) morphology, and inflammation of the synovium. Methods We investigated the prevalence of primary OA in aged, genetically diverse UM-HET3 mice. Articular cartilage (AC) integrity and SCB morphology were assessed in 182 knee joints of 22-25 months old mice using the Osteoarthritis Research Society International (OARSI) scoring system and micro-CT, respectively. Additionally, we explored the effects of methylene blue (MB) and mitoquinone (MitoQ), two agents that affect mitochondrial function, on the prevalence and progression of OA during aging. Results Aged UM-HET3 mice showed a high prevalence of primary OA in both sexes. Significant positive correlations were found between cumulative AC (cAC) scores and synovitis in both sexes, and osteophyte formation in female mice. Ectopic chondrogenesis did not show significant correlations with cAC scores. Significant direct correlations were found between AC scores and inflammatory markers in chondrocytes, including matrix metalloproteinase-13, inducible nitric oxide synthase, and the NLR family pyrin domain containing-3 inflammasome in both sexes, indicating a link between OA severity and inflammation. Additionally, markers of cell cycle arrest, such as p16 and β-galactosidase, also correlated with AC scores. In male mice, no significant correlations were found between SCB morphology traits and cAC scores, while in female mice, significant correlations were found between cAC scores and tibial SCB plate bone mineral density. Notably, MB and MitoQ treatments influenced the disease's progression in a sex-specific manner. MB treatment significantly reduced cAC scores at the medial knee joint, while MitoQ treatment reduced cAC scores, but these did not reach significance. Conclusions Our study provides comprehensive insights into the prevalence and progression of primary OA in aged UM-HET3 mice, highlighting the sex-specific effects of MB and MitoQ treatments. The correlations between AC scores and various pathological factors underscore the multifaceted nature of OA and its association with inflammation and subchondral bone changes.
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Affiliation(s)
- Sher Bahadur Poudel
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY
| | - Ryan R Ruff
- David B. Kriser Dental Center, Biostatistics Core, Department of Epidemiology and Health Promotion, New York University College of Dentistry New York, NY 10010-4086
| | - Gozde Yildirim
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY
| | - Richard A Miller
- Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI, USA
| | | | - Randy Strong
- Geriatric Research, Education and Clinical Center and Research Service, South Texas Veterans Health Care System, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies and Department of Pharmacology, The University of Texas Health Science Center, San Antonio, TX, USA
| | - Thorsten Kirsch
- Department of Orthopaedic Surgery, NYU Grossman School of Medicine, and Department of Biomedical Engineering, NYU Tandon School of Engineering, New York, NY
| | - Shoshana Yakar
- David B. Kriser Dental Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY
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Poudel SB, Ruff RR, Yildirim G, Miller RA, Harrison DE, Strong R, Kirsch T, Yakar S. Development of primary osteoarthritis during aging in genetically diverse UM-HET3 mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.12.16.571693. [PMID: 38168298 PMCID: PMC10760163 DOI: 10.1101/2023.12.16.571693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
This study investigated the prevalence and progression of primary osteoarthritis (OA) in aged UM-HET3 mice. Using the Osteoarthritis Research Society International (OARSI) scoring system, we assessed articular cartilage (AC) integrity in 182 knee joints of 22-25 months old mice. Aged UM-HET3 mice showed a high prevalence of primary OA in both sexes. Significant positive correlations were found between cumulative AC (cAC) scores and synovitis in both sexes, and osteophyte formation in female mice. Ectopic chondrogenesis did not show significant correlations with cAC scores. Significant direct correlations were found between AC scores and inflammatory markers in chondrocytes, including matrix metalloproteinase-13 (MMP-13), inducible nitric oxide synthase (iNOS), and the NLR family pyrin domain containing-3 (NLRP3) inflammasome in both sexes, indicating a link between OA severity and inflammation. Additionally, markers of cell cycle arrest, such as p16 and β-galactosidase, also correlated with AC scores. Using micro-CT, we examined the correlations between subchondral bone (SCB) morphology traits and AC scores. In male mice, no significant correlations were found between SCB morphology traits and cAC scores, while in female mice, significant correlations were found between cAC scores and tibial SCB plate bone mineral density. Finally, we explored the effects of methylene blue (MB) and mitoquinone (MitoQ), two agents that affect mitochondrial function, on the prevalence and progression of OA during aging. Notably, MB and MitoQ treatments influenced the disease's progression in a sex-specific manner. MB treatment significantly reduced cAC scores at the medial knee joint, while MitoQ treatment reduced cAC scores, but these did not reach significance. In conclusion, our study provides comprehensive insights into the prevalence and progression of primary OA in aged UM-HET3 mice, highlighting the sex-specific effects of MB and MitoQ treatments. The correlations between AC scores and various pathological factors underscore the multifaceted nature of OA and its association with inflammation and subchondral bone changes.
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Dudaric L, Dumic-Cule I, Divjak E, Cengic T, Brkljacic B, Ivanac G. Bone Remodeling in Osteoarthritis-Biological and Radiological Aspects. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1613. [PMID: 37763732 PMCID: PMC10537088 DOI: 10.3390/medicina59091613] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/24/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023]
Abstract
Among available papers published on the given subject over the last century, various terms have been used as synonyms for one, now generally accepted-osteoarthritis, in some countries called "wear and tear" or "overload arthritis". The opsolent terms-hypertrophic arthritis, degenerative arthritis, arthritis deformans and osteoarthrosis-sought to highlight the dominant clinical signs of this ubiquitous, polymorph disease of the whole osteochondral unit, which by incidence and prevalence represents one of the leading chronic conditions that cause long-term pain and incapacity for work. Numerous in vitro and in vivo research resulted in broadened acknowledgments about osteoarthritis pathophysiology and pathology on both histological and cellular levels. However, the cause of osteoarthritis is still unknown and is currently the subject of a hypothesis. In this paper, we provide a review of recent findings on biological phenomena taking place in bone tissue during osteoarthritis to the extent useful for clinical practice. Choosing a proper radiological approach is a conditio sine qua non to the early diagnosis of this entity.
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Affiliation(s)
- Luka Dudaric
- Croatia Poliklinika, Rijeka Radiology Unit, Vukovarska 7A, 51000 Rijeka, Croatia;
| | - Ivo Dumic-Cule
- Clinical Department of Diagnostic and Interventional Radiology, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia;
- Department of Nursing, University North, 104 Brigade 3, 42000 Varazdin, Croatia
| | - Eugen Divjak
- Department of Diagnostic and Interventional Radiology, University Hospital Dubrava, Avenija Gojka Suska 6, 10000 Zagreb, Croatia; (E.D.); (B.B.); (G.I.)
| | - Tomislav Cengic
- Department of Orthopedics and Traumatology, University Hospital Centre Sestre Milosrdnice, Draskoviceva 19, 10000 Zagreb, Croatia
| | - Boris Brkljacic
- Department of Diagnostic and Interventional Radiology, University Hospital Dubrava, Avenija Gojka Suska 6, 10000 Zagreb, Croatia; (E.D.); (B.B.); (G.I.)
- School of Medicine, University of Zagreb, Salata 3, 10000 Zagreb, Croatia
| | - Gordana Ivanac
- Department of Diagnostic and Interventional Radiology, University Hospital Dubrava, Avenija Gojka Suska 6, 10000 Zagreb, Croatia; (E.D.); (B.B.); (G.I.)
- School of Medicine, University of Zagreb, Salata 3, 10000 Zagreb, Croatia
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Leal Reis I, Lopes B, Sousa P, Sousa AC, Branquinho M, Caseiro AR, Pedrosa SS, Rêma A, Oliveira C, Porto B, Atayde L, Amorim I, Alvites R, Santos JM, Maurício AC. Allogenic Synovia-Derived Mesenchymal Stem Cells for Treatment of Equine Tendinopathies and Desmopathies-Proof of Concept. Animals (Basel) 2023; 13:ani13081312. [PMID: 37106875 PMCID: PMC10135243 DOI: 10.3390/ani13081312] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 03/29/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
Tendon and ligament injuries are frequent in sport horses and humans, and such injuries represent a significant therapeutic challenge. Tissue regeneration and function recovery are the paramount goals of tendon and ligament lesion management. Nowadays, several regenerative treatments are being developed, based on the use of stem cell and stem cell-based therapies. In the present study, the preparation of equine synovial membrane mesenchymal stem cells (eSM-MSCs) is described for clinical use, collection, transport, isolation, differentiation, characterization, and application. These cells are fibroblast-like and grow in clusters. They retain osteogenic, chondrogenic, and adipogenic differentiation potential. We present 16 clinical cases of tendonitis and desmitis, treated with allogenic eSM-MSCs and autologous serum, and we also include their evaluation, treatment, and follow-up. The concerns associated with the use of autologous serum as a vehicle are related to a reduced immunogenic response after the administration of this therapeutic combination, as well as the pro-regenerative effects from the growth factors and immunoglobulins that are part of its constitution. Most of the cases (14/16) healed in 30 days and presented good outcomes. Treatment of tendon and ligament lesions with a mixture of eSM-MSCs and autologous serum appears to be a promising clinical option for this category of lesions in equine patients.
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Affiliation(s)
- Inês Leal Reis
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
- Cooperativa de Ensino Superior Politécnico e Universitário (CESPU), Avenida Central de Gandra 1317, 4585-116 Gandra, Portugal
| | - Bruna Lopes
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Patrícia Sousa
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Ana Catarina Sousa
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Mariana Branquinho
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Ana Rita Caseiro
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
- University School Vasco da Gama (EUVG), Avenida José R. Sousa Fernandes, 3020-210 Coimbra, Portugal
- Vasco da Gama Research Center (CIVG), University School Vasco da Gama (EUVG), Avenida José R. Sousa Fernandes, 3020-210 Coimbra, Portugal
| | - Sílvia Santos Pedrosa
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
- Centro de Biotecnologia e Química Fina (CBQF), Laboratório Associado, Escola Superior de Biotecnologia, Universidade Católica Portuguesa, Rua de Diogo Botelho 1327, 4169-005 Porto, Portugal
| | - Alexandra Rêma
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Cláudia Oliveira
- Laboratório de Citogenética, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
| | - Beatriz Porto
- Laboratório de Citogenética, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
| | - Luís Atayde
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Irina Amorim
- Departamento de Patologia e Imunologia Molecular, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto (UP), Rua Alfredo Allen, 4200-135 Porto, Portugal
| | - Rui Alvites
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
- Cooperativa de Ensino Superior Politécnico e Universitário (CESPU), Avenida Central de Gandra 1317, 4585-116 Gandra, Portugal
| | - Jorge Miguel Santos
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
| | - Ana Colette Maurício
- Departamento de Clínicas Veterinárias, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), Universidade do Porto (UP), Rua de Jorge Viterbo Ferreira, No. 228, 4050-313 Porto, Portugal
- Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente da Universidade do Porto (ICETA), Rua D. Manuel II, Apartado 55142, 4051-401 Porto, Portugal
- Associate Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisboa, Portugal
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Sang S, Mao X, Cao Y, Liu Z, Shen Z, Li M, Jia W, Guo Z, Wang Z, Xiang C, Sun L. 3D Bioprinting Using Synovium-Derived MSC-Laden Photo-Cross-Linked ECM Bioink for Cartilage Regeneration. ACS APPLIED MATERIALS & INTERFACES 2023; 15:8895-8913. [PMID: 36779653 DOI: 10.1021/acsami.2c19058] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
In this study, inspired by the components of cartilage matrix, a photo-cross-linked extracellular matrix (ECM) bioink composed of modified proteins and polysaccharides was presented, including gelatin methacrylate, hyaluronic acid methacrylate, and chondroitin sulfate methacrylate. The systematic experiments were performed, including morphology, swelling, degradation, mechanical and rheological tests, printability analysis, biocompatibility and chondrogenic differentiation characterization, and RNA sequencing (RNA-seq). The results indicated that the photo-cross-linked ECM hydrogels possessed suitable degradation rate and excellent mechanical properties, and the three-dimensional (3D) bioprinted ECM scaffolds obtained favorable shape fidelity and improved the basic properties, biological properties, and chondrogenesis of synovium-derived MSCs (SMSCs). The strong stimulation of transforming growth factor-beta 1 (TGF-β1) enhanced the aggregation, proliferation, and differentiation of SMSCs, thereby enhancing chondrogenic ECM deposition. In vivo animal experiments and gait analysis further confirmed that the ECM scaffold combined with TGF-β1 could effectively promote cartilage regeneration and functional recovery of injured joints. To sum up, the photo-cross-linked ECM bioink for 3D printing of functional cartilage tissue may become an attractive strategy for cartilage regeneration.
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Affiliation(s)
- Shengbo Sang
- Shanxi Key Laboratory of Micro Nano Sensors & Artificial Intelligence Perception, College of Information and Computer, Taiyuan University of Technology, Taiyuan 030024, China
- Key Lab of Advanced Transducers and Intelligent Control System of the Ministry of Education, Taiyuan University of Technology, Taiyuan 030024, China
| | - Xingjia Mao
- Department of Basic Medicine Sciences, and Department of Orthopaedics of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yanyan Cao
- College of Information Science and Engineering, Hebei North University, Zhangjiakou 075000, China
| | - Zixian Liu
- Shanxi Key Laboratory of Micro Nano Sensors & Artificial Intelligence Perception, College of Information and Computer, Taiyuan University of Technology, Taiyuan 030024, China
- Key Lab of Advanced Transducers and Intelligent Control System of the Ministry of Education, Taiyuan University of Technology, Taiyuan 030024, China
| | - Zhizhong Shen
- Shanxi Key Laboratory of Micro Nano Sensors & Artificial Intelligence Perception, College of Information and Computer, Taiyuan University of Technology, Taiyuan 030024, China
- Shanxi Research Institute of 6D Artificial Intelligence Biomedical Science, Taiyuan 030031, China
| | - Meng Li
- Shanxi Key Laboratory of Micro Nano Sensors & Artificial Intelligence Perception, College of Information and Computer, Taiyuan University of Technology, Taiyuan 030024, China
- Shanxi Research Institute of 6D Artificial Intelligence Biomedical Science, Taiyuan 030031, China
| | - Wendan Jia
- Shanxi Key Laboratory of Micro Nano Sensors & Artificial Intelligence Perception, College of Information and Computer, Taiyuan University of Technology, Taiyuan 030024, China
- Shanxi Research Institute of 6D Artificial Intelligence Biomedical Science, Taiyuan 030031, China
| | - Zijian Guo
- Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Zehua Wang
- Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Chuan Xiang
- Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan 030001, China
| | - Lei Sun
- Shanxi Key Laboratory of Micro Nano Sensors & Artificial Intelligence Perception, College of Information and Computer, Taiyuan University of Technology, Taiyuan 030024, China
- Key Lab of Advanced Transducers and Intelligent Control System of the Ministry of Education, Taiyuan University of Technology, Taiyuan 030024, China
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9
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Chen L, Wei L, Su X, Qin L, Xu Z, Huang X, Chen H, Hu N. Preparation and Characterization of Biomimetic Functional Scaffold with Gradient Structure for Osteochondral Defect Repair. Bioengineering (Basel) 2023; 10:bioengineering10020213. [PMID: 36829707 PMCID: PMC9952804 DOI: 10.3390/bioengineering10020213] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/20/2023] [Accepted: 02/03/2023] [Indexed: 02/08/2023] Open
Abstract
Osteochondral (OC) defects cannot adequately repair themselves due to their sophisticated layered structure and lack of blood supply in cartilage. Although therapeutic interventions are reaching an advanced stage, current clinical therapies to repair defects are in their infancy. Among the possible therapies, OC tissue engineering has shown considerable promise, and multiple approaches utilizing scaffolds, cells, and bioactive factors have been pursued. The most recent trend in OC tissue engineering has been to design gradient scaffolds using different materials and construction strategies (such as bi-layered, multi-layered, and continuous gradient structures) to mimic the physiological and mechanical properties of OC tissues while further enabling OC repair. This review focuses specifically on design and construction strategies for gradient scaffolds and their role in the successful engineering of OC tissues. The current dilemmas in the field of OC defect repair and the efforts of tissue engineering to address these challenges were reviewed. In addition, the advantages and limitations of the typical fabrication techniques for gradient scaffolds were discussed, with examples of recent studies summarizing the future prospects for integrated gradient scaffold construction. This updated and enlightening review could provide insights into our current understanding of gradient scaffolds in OC tissue engineering.
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Affiliation(s)
| | | | | | | | | | - Xiao Huang
- Correspondence: (X.H.); (H.C.); (N.H.); Tel.: +86-023-89011202 (X.H. & H.C. & N.H.)
| | - Hong Chen
- Correspondence: (X.H.); (H.C.); (N.H.); Tel.: +86-023-89011202 (X.H. & H.C. & N.H.)
| | - Ning Hu
- Correspondence: (X.H.); (H.C.); (N.H.); Tel.: +86-023-89011202 (X.H. & H.C. & N.H.)
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10
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Sinkler MA, Furdock RJ, McMellen CJ, Calcei JG, Voos JE. Biologics, Stem Cells, Growth Factors, Platelet-Rich Plasma, Hemarthrosis, and Scaffolds May Enhance Anterior Cruciate Ligament Surgical Treatment. Arthroscopy 2023; 39:166-175. [PMID: 36370920 DOI: 10.1016/j.arthro.2022.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 11/03/2022] [Indexed: 11/11/2022]
Abstract
Biologics including mesenchymal stem cells (MSCs), growth factors, and platelet-rich plasma may enhance anterior cruciate ligament (ACL) reconstruction and even ACL primary repair. In addition, hemarthrosis after acute ACL injury represents a source of biologic factors. MSCs can differentiate into both fibroblasts and osteoblasts, potentially providing a transition between the ligament or graft and bone. MSCs also produce cytokines and growth factors necessary for cartilage, bone, ligament, and tendon regeneration. MSC sources including bone marrow, synovium, adipose tissue, ACL-remnant, patellar tendon, and umbilical cord. Also, scaffolds may represent a tool for ACL tissue engineering. A scaffold should be porous, which allows cell growth and flow of nutrients and waste, should be biocompatible, and might have mechanical properties that match the native ACL. Scaffolds have the potential to deliver bioactive molecules or stem cells. Synthetic and biologically derived scaffolds are widely available. ACL reconstruction with improved outcome, ACL repair, and ACL tissue engineering are promising goals. LEVEL OF EVIDENCE: Level V, expert opinion.
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Affiliation(s)
- Margaret A Sinkler
- Department of Orthopaedic Surgery, University Hospitals Cleveland Medical Center, Cleveland Ohio, U.S.A..
| | - Ryan J Furdock
- Department of Orthopaedic Surgery, University Hospitals Cleveland Medical Center, Cleveland Ohio, U.S.A
| | - Christopher J McMellen
- Department of Orthopaedic Surgery, University Hospitals Cleveland Medical Center, Cleveland Ohio, U.S.A
| | - Jacob G Calcei
- Department of Orthopaedic Surgery, University Hospitals Cleveland Medical Center, Cleveland Ohio, U.S.A
| | - James E Voos
- Department of Orthopaedic Surgery, University Hospitals Cleveland Medical Center, Cleveland Ohio, U.S.A
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11
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Strecanska M, Danisovic L, Ziaran S, Cehakova M. The Role of Extracellular Matrix and Hydrogels in Mesenchymal Stem Cell Chondrogenesis and Cartilage Regeneration. LIFE (BASEL, SWITZERLAND) 2022; 12:life12122066. [PMID: 36556431 PMCID: PMC9784885 DOI: 10.3390/life12122066] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/02/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022]
Abstract
Diseases associated with articular cartilage disintegration or loss are still therapeutically challenging. The traditional treatment approaches only alleviate the symptoms while potentially causing serious side effects. The limited self-renewal potential of articular cartilage provides opportunities for advanced therapies involving mesenchymal stem cells (MSCs) that are characterized by a remarkable regenerative capacity. The chondrogenic potential of MSCs is known to be regulated by the local environment, including soluble factors and the less discussed extracellular matrix (ECM) components. This review summarizes the process of chondrogenesis, and also the biological properties of the ECM mediated by mechanotransduction as well as canonical and non-canonical signaling. Our focus is also on the influence of the ECM's physical parameters, molecular composition, and chondrogenic factor affinity on the adhesion, survival, and chondrogenic differentiation of MSCs. These basic biological insights are crucial for a more precise fabrication of ECM-mimicking hydrogels to improve cartilage tissue reconstruction. Lastly, we provide an overview of hydrogel classification and characterization. We also include the results from preclinical models combining MSCs with hydrogels for the treatment of cartilage defects, to support clinical application of this construct. Overall, it is believed that the proper combination of MSCs, hydrogels, and chondrogenic factors can lead to complex cartilage regeneration.
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Affiliation(s)
- Magdalena Strecanska
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia
- Institute of Medical Biology, Genetics, and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Lubos Danisovic
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia
- Institute of Medical Biology, Genetics, and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia
| | - Stanislav Ziaran
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia
- Department of Urology, Faculty of Medicine, Comenius University, Limbova 5, 833 05 Bratislava, Slovakia
| | - Michaela Cehakova
- National Institute of Rheumatic Diseases, Nabrezie I. Krasku 4, 921 12 Piestany, Slovakia
- Institute of Medical Biology, Genetics, and Clinical Genetics, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia
- Correspondence: ; Tel.: +421-2-5935-7215
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Witoonpanich B, Jinawath A, Wongtawan T, Tawonsawatruk T. Association of synovial expression of growth and differentiation factor 5 (GDF5) with radiographic severity of knee osteoarthritis. Heliyon 2022; 8:e11798. [DOI: 10.1016/j.heliyon.2022.e11798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 09/21/2021] [Accepted: 11/14/2022] [Indexed: 11/20/2022] Open
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Yin H, Li M, Tian G, Ma Y, Ning C, Yan Z, Wu J, Ge Q, Sui X, Liu S, Zheng J, Guo W, Guo Q. The role of extracellular vesicles in osteoarthritis treatment via microenvironment regulation. Biomater Res 2022; 26:52. [PMID: 36199125 PMCID: PMC9532820 DOI: 10.1186/s40824-022-00300-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Accepted: 09/18/2022] [Indexed: 11/10/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative joint disease that is common among the middle-aged and older populations, causes patients to experience recurrent pain in their joints and negatively affects their quality of life. Currently, therapeutic options for patients with OA consist of medications to alleviate pain and treat the symptoms; however, due to typically poor outcomes, patients with advanced OA are unlikely to avoid joint replacement. In recent years, several studies have linked disrupted homeostasis of the joint cavity microenvironment to the development of OA. Recently, extracellular vesicles (EVs) have received increasing attention in the field of OA. EVs are natural nano-microcarrier materials with unique biological activity that are produced by cells through paracrine action. They are composed of lipid bilayers that contain physiologically active molecules, such as nucleic acids and proteins. Moreover, EVs may participate in local and distal intercellular and intracellular communication. EVs have also recently been shown to influence OA development by regulating biochemical factors in the OA microenvironmental. In this article, we first describe the microenvironment of OA. Then, we provide an overview of EVs, summarize the main types used for the treatment of OA, and describe their mechanisms. Next, we review clinical studies using EVs for OA treatment. Finally, the specific mechanism underlying the application of miRNA-enriched EVs in OA therapy is described.
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Affiliation(s)
- Han Yin
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Muzhe Li
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
- Department of Orthopedics, The First Affiliated Hospital of University of South China, Hengyang, 421000, China
| | - Guangzhao Tian
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
- School of Medicine, Nankai University, Tianjin, 300071, China
| | - Yang Ma
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Chao Ning
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Zineng Yan
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Jiang Wu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Qian Ge
- Huaiyin People's Hospital of Huai'an, Huai'an, 223001, China
| | - Xiang Sui
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China
| | - Shuyun Liu
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China.
| | - Jinxuan Zheng
- Department of Orthodontics, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, No.56 Linyuan Xi Road, Yuexiu District, Guangzhou, Guangdong, 510055, People's Republic of China.
| | - Weimin Guo
- Department of Orthopaedic Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-Sen University, No.58 Zhongshan Second Road, Yuexiu District, Guangzhou, 510080, Guangdong, China.
| | - Quanyi Guo
- Institute of Orthopedics, The First Medical Center, Chinese PLA General Hospital, Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries PLA, No. 28 Fuxing Road, Haidian District, Beijing, 100853, PR China.
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14
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Autologous Stem Cells for the Treatment of Chondral Injury and Disease. OPER TECHN SPORT MED 2022. [DOI: 10.1016/j.otsm.2022.150963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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15
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Kuwahara M, Akasaki Y, Goto N, Kurakazu I, Sueishi T, Toya M, Uchida T, Tsutsui T, Hirose R, Tsushima H, Nakashima Y. Fluvastatin promotes chondrogenic differentiation of adipose-derived mesenchymal stem cells by inducing bone morphogenetic protein 2. BMC Pharmacol Toxicol 2022; 23:61. [PMID: 35945639 PMCID: PMC9361648 DOI: 10.1186/s40360-022-00600-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/28/2022] [Indexed: 11/16/2022] Open
Abstract
Background Adipose-derived mesenchymal stem cells (ADMSCs) are a promising source of material source for medical regeneration of cartilage. Growth factors, including transforming growth factor-β (TGFβ) subfamily members and bone morphogenetic proteins (BMPs), play important roles in inducing and promoting chondrogenic differentiation of MSCs. However, these exogenous growth factors have some drawbacks related to their cost, biological half-life, and safety for clinical application. Several studies have reported that statins, the competitive inhibitors of 3-hydroxy-2-methylglutaryl coenzyme A (HMG-CoA) reductase, induce the expression of BMP2 in multiple cell types as the pleotropic effects. The objective of this study was to investigate the effects of fluvastatin during chondrogenic differentiation of human ADMSCs (hADMSCs). Methods The effects of fluvastatin were analyzed during chondrogenic differentiation of hADMSCs in the pellet culture without exogenous growth factors by qRT-PCR and histology. For functional studies, Noggin, an antagonist of BMPs, mevalonic acid (MVA) and geranylgeranyl pyrophosphate (GGPP), metabolites of the mevalonate pathway, ROCK inhibitor (Y27632), or RAC1 inhibitor (NSC23766) were applied to cells during chondrogenic differentiation. Furthermore, RhoA activity was measured by RhoA pulldown assay during chondrogenic differentiation with or without fluvastatin. Statistically significant differences between groups were determined by Student’s t-test or the Tukey–Kramer test. Results Fluvastatin-treated cells expressed higher levels of BMP2, SOX9, ACAN, and COL2A1 than control cells, and accumulated higher levels of glycosaminoglycans (GAGs). Noggin significantly inhibited the fluvastatin-mediated upregulation of ACAN and COL2A1. Both MVA and GGPP suppressed the effects of fluvastatin on the expressions of BMP2, SOX9, ACAN, and COL2A1. Furthermore, fluvastatin suppressed the RhoA activity, and inhibition of RhoA–ROCK signaling by Y27632 increased the expressions of BMP2, SOX9, ACAN, and COL2A1, as well as fluvastatin. Conclusions Our results suggest that fluvastatin promotes chondrogenic differentiation of hADMSCs by inducing endogenous BMP2, and that one of the mechanisms underlying the effects is inhibition of RhoA–ROCK signaling via suppression of GGPP. Fluvastatin is a safe and low-cost compound that holds promise for use in transplantation of hADMSCs for cartilage regeneration. Supplementary Information The online version contains supplementary material available at 10.1186/s40360-022-00600-7.
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Affiliation(s)
- Masanari Kuwahara
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan
| | - Yukio Akasaki
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan.
| | - Norio Goto
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan
| | - Ichiro Kurakazu
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan
| | - Takuya Sueishi
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan
| | - Masakazu Toya
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan
| | - Taisuke Uchida
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan
| | - Tomoaki Tsutsui
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan
| | - Ryota Hirose
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan
| | - Hidetoshi Tsushima
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan
| | - Yasuharu Nakashima
- Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka city, Fukuoka, 812-8582, Japan
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Fan WJ, Liu D, Pan LY, Wang WY, Ding YL, Zhang YY, Ye RX, Zhou Y, An SB, Xiao WF. Exosomes in osteoarthritis: Updated insights on pathogenesis, diagnosis, and treatment. Front Cell Dev Biol 2022; 10:949690. [PMID: 35959489 PMCID: PMC9362859 DOI: 10.3389/fcell.2022.949690] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 07/04/2022] [Indexed: 01/09/2023] Open
Abstract
Osteoarthritis (OA) has remained a prevalent public health problem worldwide over the past decades. OA is a global challenge because its specific pathogenesis is unclear, and no effective disease-modifying drugs are currently available. Exosomes are small and single-membrane vesicles secreted via the formation of endocytic vesicles and multivesicular bodies (MVBs), which are eventually released when MVBs fuse with the plasma membrane. Exosomes contain various integral surface proteins derived from cells, intercellular proteins, DNAs, RNAs, amino acids, and metabolites. By transferring complex constituents and promoting macrophages to generate chemokines and proinflammatory cytokines, exosomes function in pathophysiological processes in OA, including local inflammation, cartilage calcification and degradation of osteoarthritic joints. Exosomes are also detected in synovial fluid and plasma, and their levels continuously change with OA progression. Thus, exosomes, specifically exosomal miRNAs and lncRNAs, potentially represent multicomponent diagnostic biomarkers for OA. Exosomes derived from various types of mesenchymal stem cells and other cell or tissue types affect angiogenesis, inflammation, and bone remodeling. These exosomes exhibit promising capabilities to restore OA cartilage, attenuate inflammation, and balance cartilage matrix formation and degradation, thus demonstrating therapeutic potential in OA. In combination with biocompatible and highly adhesive materials, such as hydrogels and cryogels, exosomes may facilitate cartilage tissue engineering therapies for OA. Based on numerous recent studies, we summarized the latent mechanisms and clinical value of exosomes in OA in this review.
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Affiliation(s)
- Wen-Jin Fan
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Di Liu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Lin-Yuan Pan
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China
| | - Wei-Yang Wang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yi-Lan Ding
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yue-Yao Zhang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Rui-Xi Ye
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yang Zhou
- Department of Clinical Nursing, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Yang Zhou, ; Sen-Bo An, ; Wen-Feng Xiao,
| | - Sen-Bo An
- Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China,*Correspondence: Yang Zhou, ; Sen-Bo An, ; Wen-Feng Xiao,
| | - Wen-Feng Xiao
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Yang Zhou, ; Sen-Bo An, ; Wen-Feng Xiao,
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MacIver MA, Dobson LK, Gregory CA, Muneoka K, Saunders WB. A three-dimensional (3D), serum-free, Collagen Type I system for chondrogenesis of canine bone marrow-derived multipotent stromal cells (cMSCs). PLoS One 2022; 17:e0269571. [PMID: 35679245 PMCID: PMC9182251 DOI: 10.1371/journal.pone.0269571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/19/2022] [Indexed: 12/03/2022] Open
Abstract
The dog is an underrepresented large animal translational model for orthopedic cell-based tissue engineering. While chondrogenic differentiation of canine multipotent stromal cells (cMSCs) has been reported using the classic micromass technique, cMSCs respond inconsistently to this method. The objectives of this study were to develop a three-dimensional (3D), serum-free, Collagen Type I system to facilitate cMSC chondrogenesis and, once established, to determine the effect of chondrogenic growth factors on cMSC chondrogenesis. Canine MSCs were polymerized in 100 μL Collagen Type I gels (5 mg/mL) at 1 x 106 cells/construct. Constructs were assessed using morphometry, live/dead staining, and histology in 10 various chondrogenic media. Four media were selected for additional in-depth analyses via lactate dehydrogenase release, total glycosaminoglycan content, qPCR (COL1A1, COL2A, SOX9, ACAN, BGLAP and SP7), immunofluorescence, and TUNEL staining. In the presence of dexamethasone and transforming growth factor-β3 (TGF-β3), both bone morphogenic protein-2 (BMP-2) and basic fibroblast growth factor (bFGF) generated larger chondrogenic constructs, although BMP-2 was required to achieve histologic characteristics of chondrocytes. Chondrogenic medium containing dexamethasone, TGF-β3, BMP-2 and bFGF led to a significant decrease in lactate dehydrogenase release at day 3 and glycosaminoglycan content was significantly increased in these constructs at day 3, 10, and 21. Both osteogenic and chondrogenic transcripts were induced in response to dexamethasone, TGF-β3, BMP-2 and bFGF. Collagen Type II and X were detected in all groups via immunofluorescence. Finally, TUNEL staining was positive in constructs lacking BMP-2 or bFGF. In conclusion, the 3D, serum-free, Collagen Type-I assay described herein proved useful in assessing cMSC differentiation and will serve as a productive system to characterize cMSCs or to fabricate tissue engineering constructs for clinical use.
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Affiliation(s)
- Melissa A. MacIver
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America
| | - Lauren K. Dobson
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America
| | - Carl A. Gregory
- Department of Molecular and Cellular Medicine, Texas A&M College of Medicine, Texas A&M University, College Station, Texas, United States of America
| | - Ken Muneoka
- Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America
| | - W. Brian Saunders
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, United States of America
- * E-mail:
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Miura Y, Endo K, Komori K, Sekiya I. Clearance of senescent cells with ABT-263 improves biological functions of synovial mesenchymal stem cells from osteoarthritis patients. Stem Cell Res Ther 2022; 13:222. [PMID: 35658936 PMCID: PMC9166575 DOI: 10.1186/s13287-022-02901-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/14/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Osteoarthritis (OA) is an age-related joint disease characterized by progressive cartilage loss. Synovial mesenchymal stem cells (MSCs) are anticipated as a cell source for OA treatment; however, synovial MSC preparations isolated from OA patients contain many senescent cells that inhibit cartilage regeneration through their senescence-associated secretory phenotype (SASP) and poor chondrogenic capacity. The aim of this study was to improve the biological function of OA synovial MSCs by removing senescent cells using the senolytic drug ABT-263. METHODS We pretreated synovial MSCs derived from 5 OA patients with ABT-263 for 24 h and then evaluated senescence-associated beta-galactosidase (SA-β-gal) activity, B cell lymphoma 2 (BCL-2) activity, apoptosis, surface antigen expression, colony formation ability, and multipotency. RESULTS The ABT-263 pretreatment significantly decreased the percentage of SA-β-gal-positive cells and BCL-2 expression and induced early- and late-stage apoptosis. Cleaved caspase-3 was expressed in SA-β-gal-positive cells. The pretreated MSCs formed greater numbers of colonies with larger diameters. The expression rate of CD34 was decreased in the pretreated cells. Differentiation assays revealed that ABT-263 pretreatment enhanced the adipogenic and chondrogenic capabilities of OA synovial MSCs. In chondrogenesis, the pretreated cells produced greater amounts of glycosaminoglycan and type II collagen and showed lower expression of senescence markers (p16 and p21) and SASP factors (MMP-13 and IL-6) and smaller amounts of type I collagen. CONCLUSION Pretreatment of synovial MSCs from OA patients with ABT-263 can improve the function of the cells by selectively eliminating senescent cells. These findings indicate that ABT-263 could hold promise for the development of effective cell-based OA therapy.
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Affiliation(s)
- Yugo Miura
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Kentaro Endo
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
| | - Keiichiro Komori
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
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Tang G, Asou Y, Matsumura E, Nakagawa Y, Miyatake K, Katagiri H, Nakamura T, Koga H, Komori K, Sekiya I, Ezura Y, Tsuji K. Short cytoplasmic isoform of IL1R1/CD121a mediates IL1β induced proliferation of synovium-derived mesenchymal stem/stromal cells through ERK1/2 pathway. Heliyon 2022; 8:e09476. [PMID: 35647352 PMCID: PMC9133583 DOI: 10.1016/j.heliyon.2022.e09476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/17/2022] [Accepted: 05/13/2022] [Indexed: 11/03/2022] Open
Abstract
Objectives IL1β enhances proliferation of synovial mesenchymal stem/stromal cells (synMSCs) although they don't express its receptor, IL1R1/CD121a, on the cell surface. This study was aimed to elucidate the underlying mechanisms of IL1β-mediated growth promotion. Methods Human synMSCs were isolated from the suprapatellar synovial membrane. Cell proliferation was measured by MTT. Flowcytometric analyses were performed for surface antigen expression. Intracellular signaling pathway was analyzed by western blotting, immunocytochemistry and Q-PCR. Results IL1β enhanced proliferation through IL1R1/CD121a because IL1 receptor antagonist (IL1Ra) completely inhibited it. Expression analyses indicated that a short isoform of IL1R1/CD121a is expressed in synMSCs. Immunocytochemistry indicated that IL1R1/CD121a was majorly localized to the cytoplasm. Western blotting indicated that IL1β induced delayed timing of the ERK1/2 phosphorylation and IκBα degradation in synMSCs. Q-PCR analyses for IL1β-target genes indicated that cyclin D was specifically downregulated by a MAPK/ERK inhibitor, U0126, but not by a NFκB inhibitor, TPCA-1. In contrast, the expression of inflammatory cytokines such as IL1α and IL6 are significantly decreased by TPCA-1 but less effectively decreased by U0126. Conclusion Our data indicated that the cytoplasmic IL1R1/CD121a transduced IL1β signal in synMSCs. And the growth-promoting effect of IL1β can be separated from its inflammatory cytokine-inducing function in synMSCs.
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Affiliation(s)
- Guo Tang
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshinori Asou
- Department of Nano-Bioscience, Tokyo Medical and Dental University, Tokyo, Japan
| | - Etsuko Matsumura
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yusuke Nakagawa
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazumasa Miyatake
- Department of Cartilage Regeneration, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroki Katagiri
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Tomomasa Nakamura
- Department of Cartilage Regeneration, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiichiro Komori
- Center for Stem Cells and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ichiro Sekiya
- Center for Stem Cells and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoich Ezura
- Department of Joint Surgery and Sports Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kunikazu Tsuji
- Department of Nano-Bioscience, Tokyo Medical and Dental University, Tokyo, Japan
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20
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Mao B, Zhang Z, Lai S, Zhang K, Li J, Fu W. Demineralized Cortical Bone Matrix Augmented With Peripheral Blood-Derived Mesenchymal Stem Cells for Rabbit Medial Meniscal Reconstruction. Front Bioeng Biotechnol 2022; 10:855103. [PMID: 35573229 PMCID: PMC9091599 DOI: 10.3389/fbioe.2022.855103] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 04/12/2022] [Indexed: 11/24/2022] Open
Abstract
Tissue engineering is a promising treatment strategy for meniscal regeneration after meniscal injury. However, existing scaffold materials and seed cells still have many disadvantages. The objective of the present study is to explore the feasibility of peripheral blood-derived mesenchymal stem cells (PBMSCs) augmented with demineralized cortical bone matrix (DCBM) pretreated with TGF-β3 as a tissue-engineered meniscus graft and the repair effect. PBMSCs were collected from rabbit peripheral blood and subjected to three-lineage differentiation and flow cytometry identification. DCBM was prepared by decalcification, decellularization, and cross-linking rabbit cortical bone. Various characteristics such as biomechanical properties, histological characteristics, microstructure and DNA content were characterized. The cytotoxicity and the effects of DCBM on the adhesion and migration of PBMSCs were evaluated separately. The meniscus-forming ability of PBMSCs/DCBM complex in vitro induced by TGF-β3 was also evaluated at the molecular and genetic levels, respectively. Eventually, the present study evaluated the repair effect and cartilage protection effect of PBMSCs/DCBM as a meniscal graft in a rabbit model of medial meniscal reconstruction in 3 and 6 months. The results showed PBMSCs positively express CD29 and CD44, negatively express CD34 and CD45, and have three-lineage differentiation ability, thus can be used as tissue engineering meniscus seed cells. After the sample procedure, the cell and DNA contents of DCBM decreased, the tensile modulus did not decrease significantly, and the DCBM had a pore structure and no obvious cytotoxicity. PBMSCs could adhere and grow on the scaffold. Under induction of TGF-β3, PBMSCs/DCBM composites expressed glycosaminoglycan (GAG), and the related gene expression also increased. The results of the in vivo experiments that the PBMSCs/DCBM group had a better repair effect than the DCBM group and the control group at both 12 and 24 weeks, and the protective effect on cartilage was also better. Therefore, the application of DCBM augmented with PBMSCs for meniscus injury treatment is a preferred option for tissue-engineered meniscus.
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Affiliation(s)
- Beini Mao
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Zhong Zhang
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
- Department of Orthopaedics, No.3 People’s Hospital of Chengdu, Chengdu, China
| | - Sike Lai
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Kaibo Zhang
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Jian Li
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
| | - Weili Fu
- Department of Orthopedics, Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, China
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21
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Yen BL, Liu K, Sytwu H, Yen M. Clinical implications of differential functional capacity between tissue‐specific human mesenchymal stromal/stem cells. FEBS J 2022. [DOI: 10.1111/febs.16438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 01/30/2022] [Accepted: 03/16/2022] [Indexed: 11/28/2022]
Affiliation(s)
- B. Linju Yen
- Regenerative Medicine Research Group Institute of Cellular & System Medicine National Health Research Institutes (NHRI) Zhunan Taiwan
- Department of Obstetrics & Gynecology Cathay General Hospital Shiji New Taipei City Taiwan
| | - Ko‐Jiunn Liu
- National Institute of Cancer Research NHRI Zhunan Taiwan
- Institute of Clinical Pharmacy & Pharmaceutical Sciences National Cheng Kung University Tainan Taiwan
- School of Medical Laboratory Science and Biotechnology Taipei Medical University Taiwan
| | - Huey‐Kang Sytwu
- National Institute of Infectious Diseases & Vaccinology NHRI Zhunan Taiwan
- Graduate Institute of Microbiology & Immunology National Defense Medical Center Taipei Taiwan
| | - Men‐Luh Yen
- Department of Obstetrics & Gynecology National Taiwan University (NTU) Hospital & College of Medicine NTU Taipei Taiwan
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22
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De Kinderen P, Meester J, Loeys B, Peeters S, Gouze E, Woods S, Mortier G, Verstraeten A. Differentiation of Induced Pluripotent Stem Cells Into Chondrocytes: Methods and Applications for Disease Modeling and Drug Discovery. J Bone Miner Res 2022; 37:397-410. [PMID: 35124831 DOI: 10.1002/jbmr.4524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 01/25/2022] [Accepted: 02/01/2022] [Indexed: 11/11/2022]
Abstract
Induced pluripotent stem cell (iPSC) technology allows pathomechanistic and therapeutic investigation of human heritable disorders affecting tissue types whose collection from patients is difficult or even impossible. Among them are cartilage diseases. Over the past decade, iPSC-chondrocyte disease models have been shown to exhibit several key aspects of known disease mechanisms. Concurrently, an increasing number of protocols to differentiate iPSCs into chondrocytes have been published, each with its respective (dis)advantages. In this review we provide a comprehensive overview of the different differentiation approaches, the hitherto described iPSC-chondrocyte disease models and mechanistic and/or therapeutic insights that have been derived from their investigation, and the current model limitations. Key lessons are that the most appropriate differentiation approach is dependent upon the cartilage disease under investigation and that further optimization is still required to recapitulate the in vivo cartilage. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Pauline De Kinderen
- Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - Josephina Meester
- Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - Bart Loeys
- Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.,Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Silke Peeters
- Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - Elvire Gouze
- Université Côte d'Azur, CNRS, Inserm, iBV, Nice, France
| | - Steven Woods
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Geert Mortier
- Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
| | - Aline Verstraeten
- Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium
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Jeyaraman M, Muthu S, Jeyaraman N, Ranjan R, Jha SK, Mishra P. Synovium Derived Mesenchymal Stromal Cells (Sy-MSCs): A Promising Therapeutic Paradigm in the Management of Knee Osteoarthritis. Indian J Orthop 2022; 56:1-15. [PMID: 35070137 PMCID: PMC8748553 DOI: 10.1007/s43465-021-00439-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 06/03/2021] [Indexed: 02/05/2023]
Abstract
Synovium-derived mesenchymal stromal cell (Sy-MSC) is a newer member of the mesenchymal stromal cell families. The first successful demonstration of the mesenchymal stromal cell from the human synovial membrane was done in 2001 and since then its potential role for musculoskeletal regeneration has been keenly documented. The regenerative effects of Sy-MSCs are through paracrine signaling, direct cell-cell interactions, and extracellular vehicles. Sy-MSCs possess superior chondrogenicity than other sources of mesenchymal stromal cells. This article aims to outline the advancement of synovium-derived mesenchymal stromal cells along with a specific insight into the application for managing osteoarthritis knee.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh India
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
- International Association of Stemcell and Regenerative Medicine (IASRM), New Delhi, India
| | - Sathish Muthu
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
- International Association of Stemcell and Regenerative Medicine (IASRM), New Delhi, India
- Department of Orthopaedics, Government Medical College & Hospital, Dindigul, Tamil Nadu India
| | - Naveen Jeyaraman
- International Association of Stemcell and Regenerative Medicine (IASRM), New Delhi, India
- Department of Orthopaedics, Kasturba Medical College, MAHE University, Manipal, Karnataka India
| | - Rajni Ranjan
- Department of Orthopaedics, School of Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh India
| | - Saurabh Kumar Jha
- Department of Biotechnology, School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh India
- International Association of Stemcell and Regenerative Medicine (IASRM), New Delhi, India
| | - Prabhu Mishra
- International Association of Stemcell and Regenerative Medicine (IASRM), New Delhi, India
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24
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Sun Z, Xu X, Lv Z, Li J, Shi T, Sun H, Sun K, Tan G, Yan W, Yang YX, Wu R, Xu J, Guo H, Jiang Q, Shi D. Intraarticular injection of SHP2 inhibitor SHP099 promotes the repair of rabbit full-thickness cartilage defect. J Orthop Translat 2022; 32:112-120. [PMID: 35228993 PMCID: PMC8857578 DOI: 10.1016/j.jot.2022.01.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 01/06/2022] [Accepted: 01/13/2022] [Indexed: 11/19/2022] Open
Abstract
Background Cartilage repair has been a challenge in the field of orthopaedics for decades, highlighting the significance of investigating potential therapeutic drugs. In this study, we explored the effect of the SHP2 inhibitor SHP099, a small-molecule drug, on cartilage repair. Methods Human synovial mesenchymal stem cells (SMSCs) were isolated, and their three-way differentiation potential was examined. After treatment with chondrogenic medium, the chondrogenic effect of SHP099 on SMSCs was examined by western blot, qPCR, and immunofluorescence (IF). Micro-mass culture was also used to detect the effect of SHP099. To explore the chondrogenic effects of SHP099 in vivo, full-thickness cartilage defects with microfractures were constructed in the right femoral trochlea of New Zealand White rabbits. Intraarticular injection of SHP099 or normal saline was performed twice a week for 6 weeks. Cartilage repair was evaluated by haematoxylin and eosin (HE) staining and safranin O/fast green staining. Immunohistochemistry (IHC) for collagen II (COL2) was also conducted to verify the abundance of cartilage extracellular matrix after SHP099 treatment. The mechanism involving yes-associated protein (YAP) and WNT signalling was investigated in vitro. Results SMSCs isolated from human synovium have optimal multi-differentiation potential. SHP099 increased chondrogenic marker (SOX9, COL2) expression and decreased hypertrophic marker (COL10, RUNX2) expression in SMSCs. In micro-mass culture, the SHP099-induced cartilage tissues had a better result of Safranin O and Toluidine blue staining and are enriched in cartilage-specific collagen II. Inhibition of YAP and WNT signalling was also observed. Moreover, compared to the normal saline group at 6 weeks, intraarticular injection of SHP099 resulted in better defect filling, forming increased hyaline cartilage-like tissue with higher levels of glycosaminoglycan (GAG) and COL2. Conclusion SHP099 promotes the repair of rabbit full-thickness cartilage defects, representing a potential therapeutic drug for cartilage repair. The Translational potential of this article This study provides evidence that SHP2 inhibition promotes chondrogenesis and the repair of cartilage in defect area, which could be a novel therapeutic approach for cartilage repair.
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Affiliation(s)
- Ziying Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Xingquan Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Zhongyang Lv
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Jiawei Li
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Tianshu Shi
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Heng Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Kuoyang Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Guihua Tan
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Wenqiang Yan
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Yannick Xiaofan Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Drum Tower of Clinical Medicine, Nanjing Medical University, Nanjing, 210008, Jiangsu, PR China
| | - Rui Wu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Jia Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Drum Tower of Clinical Medicine, Nanjing Medical University, Nanjing, 210008, Jiangsu, PR China
| | - Hu Guo
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Qing Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
| | - Dongquan Shi
- State Key Laboratory of Pharmaceutical Biotechnology, Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China
- Laboratory for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093, Jiangsu, PR China
- Corresponding author. Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, Jiangsu, PR China.
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Lee J, Jang S, Kwon J, Oh TI, Lee E. Comparative Evaluation of Synovial Multipotent Stem Cells and Meniscal Chondrocytes for Capability of Fibrocartilage Reconstruction. Cartilage 2021; 13:980S-990S. [PMID: 32748647 PMCID: PMC8804725 DOI: 10.1177/1947603520946367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
OBJECTIVE Meniscus tissue is composed of highly aligned type I collagen embedded with cartilaginous matrix. This histological feature endows mechanical properties, such as tensile strength along the direction of the collagen alignment and endurance to compressive load induced by weight bearing. The main objective of this study was to compare the fibrocartilage construction capability of different cell sources in the presence of mechanical stimuli. DESIGN Synovial multipotent stem cells (SvMSCs) and meniscal chondrocytes (MCs) from immature and mature rabbits were maintained under similar conditions for comparative evaluation of growth characteristics and senescence tendency. The differentiation potential of cell sources, including fibrocartilage generation, were comparatively evaluated. To determine the capability of fibrocartilage generation, cultured cell sheets were rolled up to produce cable-form tissue and subjected to chondrogenic induction in the presence or absence of static tension. RESULTS Although SvMSCs showed superior cell growth characteristics during in vitro cell expansion, senescence-associated β-galactosidase expression was consistently higher, compared with MCs. MCs showed glycosaminoglycan (GAG)-rich matrix formation during default in vitro chondrogenesis. While application of static tension significantly reduced GAG production, MCs continued to show robust tissue growth. SvMSCs showed inferior chondrogenic differentiation and diminished tissue growth in the presence of static tension. CONCLUSIONS While SvMSCs produced fibrous tissue during default in vitro chondrogenesis, their fibrocartilage generation potential in the presence of static tension was significantly lower, compared with MCs. Our results support evaluation of cellular response to tensile stimulus as a decisive factor in determining the ideal cell source for fibrocartilage reconstruction.
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Affiliation(s)
- Jisoo Lee
- Department of Medical Engineering,
Graduate School, Kyung Hee University, Seoul, South Korea
| | - Seoyoung Jang
- Department of Medical Engineering,
Graduate School, Kyung Hee University, Seoul, South Korea
| | - JunPyo Kwon
- Department of Medical Engineering,
Graduate School, Kyung Hee University, Seoul, South Korea
| | - Tong In Oh
- Department of Biomedical
Engineering, School of Medicine, Kyung Hee University, Seoul, South
Korea
| | - EunAh Lee
- Impedance Imaging Research Center,
Kyung Hee University, Seoul, South Korea
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Jeyaraman M, Muthu S, Ganie PA. Does the Source of Mesenchymal Stem Cell Have an Effect in the Management of Osteoarthritis of the Knee? Meta-Analysis of Randomized Controlled Trials. Cartilage 2021; 13:1532S-1547S. [PMID: 32840122 PMCID: PMC8808923 DOI: 10.1177/1947603520951623] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
STUDY DESIGN Meta-analysis. OBJECTIVES To compare the efficacy and safety of bone marrow(BM)-derived mesenchymal stem cell(MSCs) and adipose-derived(AD) MSCs in the management of osteoarthritis of knee from randomized controlled trials(RCTs) available in the literature. MATERIALS AND METHODS We conducted electronic database searche from PubMed, Embase, and Cochrane Library till May 2020 for RCTs analyzing the efficacy and safety of MSCs in management of osteoarthritis of knee. Visual Analog Score(VAS) for Pain, Western Ontario McMaster Universities Osteoarthritis Index(WOMAC), Lysholm Knee Scale(Lysholm), Whole-Organ Magnetic Resonance Imaging Score(WORMS), Knee Osteoarthritis Outcome Score(KOOS), and adverse events were the outcomes analyzed. Analysis was performed in R platform using OpenMeta[Analyst] software. RESULTS Nineteen studies involving 811 patients were included for analysis. None of the studies compared the source of MSCs for osteoarthritis of knee and results were obtained by pooled data analysis of both sources. At 6 months, AD-MSCs showed significantly better VAS(P<0.001,P=0.069) and WOMAC(P=0.134,P=0.441) improvement than BM-MSCs, respectively, compared to controls. At 1 year, AD-MSCs outperformed BM-MSCs compared to their control in measures like WOMAC(P=0.007,P=0.150), KOOS(P<0.001;P=0.658), and WORMS(P<0.001,P=0.041), respectively. Similarly at 24 months, AD-MSCs showed significantly better Lysholm score(P=0.037) than BM-MSCs(P=0.807) although VAS improvement was better with BM-MSCs at 24 months(P<0.001). There were no significant adverse events with either of the MSCs compared to their controls. CONCLUSION Our analysis establishes the efficacy, safety, and superiority of AD-MSC transplantation, compared to BM-MSC, in the management of osteoarthritis of knee from available literature. Further RCTs are needed to evaluate them together with standardized doses.
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Affiliation(s)
- Madhan Jeyaraman
- Department of Orthopaedics, School of
Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh,
India
| | - Sathish Muthu
- Government Hospital, Velayuthampalayam,
Karur, Tamil Nadu, India
- Sathish Muthu, Government Hospital,
Velayuthampalayam, Pugalur Road, Karur, Tamil Nadu 639117, India.
| | - Parvez Ahmad Ganie
- Department of Orthopaedics, School of
Medical Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh,
India
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27
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Jaibaji M, Jaibaji R, Volpin A. Mesenchymal Stem Cells in the Treatment of Cartilage Defects of the Knee: A Systematic Review of the Clinical Outcomes. Am J Sports Med 2021; 49:3716-3727. [PMID: 33555942 DOI: 10.1177/0363546520986812] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Osteochondral lesions are a common clinical problem and their management has been historically challenging. Mesenchymal stem cells have the potential to differentiate into chondrocytes and thus restore hyaline cartilage to the defect, theoretically improving clincal outcomes in these patients. They can also be harvested with minimal donor site morbidity. PURPOSE To assess the clinical and functional outcomes of mesenchymal stem cell implantation to treat isolated osteochondral defects of the knee. A secondary purpose is to assess the quality of the current available evidence as well as the radiological and histological outcomes. We also reviewed the cellular preparation and operative techniques for implantation. STUDY DESIGN Systematic review. METHODS A comprehensive literature search of 4 databases was carried out: CINAHL, Embase, MEDLINE, and PubMed. We searched for clinical studies reporting the outcomes on a minimum of 5 patients with at least 12 months of follow-up. Clinical, radiological, and histological outcomes were recorded. We also recorded demographics, stem cell source, culture technique, and operative technique. Methodological quality of each study was assessed using the modified Coleman methodology score, and risk of bias for the randomized controlled studies was assessed using the Cochrane Collaboration tool. RESULTS Seventeen studies were found, encompassing 367 patients. The mean patient age was 35.1 years. Bone marrow was the most common source of stem cells utilized. Mesenchymal stem cell therapy consistently demonstrated good short- to medium-term outcomes in the studies reviewed with no serious adverse events being recorded. There was significant heterogeneity in cell harvesting and preparation as well as in the reporting of outcomes. CONCLUSION Mesenchymal stem cells demonstrated a clinically relevant improvement in outcomes in patients with osteochondral defects of the knee. More research is needed to establish an optimal treatment protocol, long-term outcomes, and superiority over other therapies. REGISTRATION CRD42020179391 (PROSPERO).
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Affiliation(s)
- Monketh Jaibaji
- Division of Interventional Sciences, University College London, London, UK
| | - Rawan Jaibaji
- Division of Interventional Sciences, University College London, London, UK
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Urlić I, Ivković A. Cell Sources for Cartilage Repair-Biological and Clinical Perspective. Cells 2021; 10:cells10092496. [PMID: 34572145 PMCID: PMC8468484 DOI: 10.3390/cells10092496] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/14/2021] [Accepted: 09/16/2021] [Indexed: 01/04/2023] Open
Abstract
Cell-based therapy represents a promising treatment strategy for cartilage defects. Alone or in combination with scaffolds/biological signals, these strategies open many new avenues for cartilage tissue engineering. However, the choice of the optimal cell source is not that straightforward. Currently, various types of differentiated cells (articular and nasal chondrocytes) and stem cells (mesenchymal stem cells, induced pluripotent stem cells) are being researched to objectively assess their merits and disadvantages with respect to the ability to repair damaged articular cartilage. In this paper, we focus on the different cell types used in cartilage treatment, first from a biological scientist’s perspective and then from a clinician’s standpoint. We compare and analyze the advantages and disadvantages of these cell types and offer a potential outlook for future research and clinical application.
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Affiliation(s)
- Inga Urlić
- Department of Biology, Faculty of Science, University of Zagreb, 10000 Zagreb, Croatia
- Correspondence: (I.U.); (A.I.)
| | - Alan Ivković
- Department of Orthopaedic Surgery, University Hospital Sveti Duh, 10000 Zagreb, Croatia
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Department of Clinical Medicine, University of Applied Health Sciences, 10000 Zagreb, Croatia
- Correspondence: (I.U.); (A.I.)
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Li Z, Huang Z, Bai L. Cell Interplay in Osteoarthritis. Front Cell Dev Biol 2021; 9:720477. [PMID: 34414194 PMCID: PMC8369508 DOI: 10.3389/fcell.2021.720477] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 07/14/2021] [Indexed: 01/15/2023] Open
Abstract
Osteoarthritis (OA) is a common chronic disease and a significant health concern that needs to be urgently solved. OA affects the cartilage and entire joint tissues, including the subchondral bone, synovium, and infrapatellar fat pads. The physiological and pathological changes in these tissues affect the occurrence and development of OA. Understanding complex crosstalk among different joint tissues and their roles in OA initiation and progression is critical in elucidating the pathogenic mechanism of OA. In this review, we begin with an overview of the role of chondrocytes, synovial cells (synovial fibroblasts and macrophages), mast cells, osteoblasts, osteoclasts, various stem cells, and engineered cells (induced pluripotent stem cells) in OA pathogenesis. Then, we discuss the various mechanisms by which these cells communicate, including paracrine signaling, local microenvironment, co-culture, extracellular vesicles (exosomes), and cell tissue engineering. We particularly focus on the therapeutic potential and clinical applications of stem cell-derived extracellular vesicles, which serve as modulators of cell-to-cell communication, in the field of regenerative medicine, such as cartilage repair. Finally, the challenges and limitations related to exosome-based treatment for OA are discussed. This article provides a comprehensive summary of key cells that might be targets of future therapies for OA.
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Affiliation(s)
- Zihao Li
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ziyu Huang
- Foreign Languages College, Shanghai Normal University, Shanghai, China
| | - Lunhao Bai
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China
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30
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Xu Y, Zhang WX, Wang LN, Ming YQ, Li YL, Ni GX. Stem cell therapies in tendon-bone healing. World J Stem Cells 2021; 13:753-775. [PMID: 34367476 PMCID: PMC8316867 DOI: 10.4252/wjsc.v13.i7.753] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/08/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023] Open
Abstract
Tendon-bone insertion injuries such as rotator cuff and anterior cruciate ligament injuries are currently highly common and severe. The key method of treating this kind of injury is the reconstruction operation. The success of this reconstructive process depends on the ability of the graft to incorporate into the bone. Recently, there has been substantial discussion about how to enhance the integration of tendon and bone through biological methods. Stem cells like bone marrow mesenchymal stem cells (MSCs), tendon stem/progenitor cells, synovium-derived MSCs, adipose-derived stem cells, or periosteum-derived periosteal stem cells can self-regenerate and potentially differentiate into different cell types, which have been widely used in tissue repair and regeneration. Thus, we concentrate in this review on the current circumstances of tendon-bone healing using stem cell therapy.
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Affiliation(s)
- Yue Xu
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Wan-Xia Zhang
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Li-Na Wang
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Yue-Qing Ming
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Yu-Lin Li
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Guo-Xin Ni
- School of Sports Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
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31
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Chijimatsu R, Miwa S, Okamura G, Miyahara J, Tachibana N, Ishikura H, Higuchi J, Maenohara Y, Tsuji S, Sameshima S, Takagi K, Nakazato K, Kawaguchi K, Yamagami R, Inui H, Taketomi S, Tanaka S, Saito T. Divergence in chondrogenic potential between in vitro and in vivo of adipose- and synovial-stem cells from mouse and human. Stem Cell Res Ther 2021; 12:405. [PMID: 34266496 PMCID: PMC8281654 DOI: 10.1186/s13287-021-02485-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Somatic stem cell transplantation has been performed for cartilage injury, but the reparative mechanisms are still conflicting. The chondrogenic potential of stem cells are thought as promising features for cartilage therapy; however, the correlation between their potential for chondrogenesis in vitro and in vivo remains undefined. The purpose of this study was to investigate the intrinsic chondrogenic condition depends on cell types and explore an indicator to select useful stem cells for cartilage regeneration. METHODS The chondrogenic potential of two different stem cell types derived from adipose tissue (ASCs) and synovium (SSCs) of mice and humans was assessed using bone morphogenic protein-2 (BMP2) and transforming growth factor-β1 (TGFβ1). Their in vivo chondrogenic potential was validated through transplantation into a mouse osteochondral defect model. RESULTS All cell types showed apparent chondrogenesis under the combination of BMP2 and TGFβ1 in vitro, as assessed by the formation of proteoglycan- and type 2 collagen (COL2)-rich tissues. However, our results vastly differed with those observed following single stimulation among species and cell types; apparent chondrogenesis of mouse SSCs was observed with supplementation of BMP2 or TGFβ1, whereas chondrogenesis of mouse ASCs and human SSCs was observed with supplementation of BMP2 not TGFβ1. Human ASCs showed no obvious chondrogenesis following single stimulation. Mouse SSCs showed the formation of hyaline-like cartilage which had less fibrous components (COL1/3) with supplementation of TGFβ1. However, human cells developed COL1/3+ tissues with all treatments. Transcriptomic analysis for TGFβ receptors and ligands of cells prior to chondrogenic induction did not indicate their distinct reactivity to the TGFβ1 or BMP2. In the transplanted site in vivo, mouse SSCs formed hyaline-like cartilage (proteoglycan+/COL2+/COL1-/COL3-) but other cell types mainly formed COL1/3-positive fibrous tissues in line with in vitro reactivity to TGFβ1. CONCLUSION Optimal chondrogenic factors driving chondrogenesis from somatic stem cells are intrinsically distinct among cell types and species. Among them, the response to TGFβ1 may possibly represent the fate of stem cells when locally transplanted into cartilage defects.
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Affiliation(s)
- Ryota Chijimatsu
- Bone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Satoshi Miwa
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Junya Miyahara
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naohiro Tachibana
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hisatoshi Ishikura
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junya Higuchi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yuji Maenohara
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | | | - Shin Sameshima
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kentaro Takagi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Keiu Nakazato
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kohei Kawaguchi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryota Yamagami
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Inui
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Shuji Taketomi
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Sakae Tanaka
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Taku Saito
- Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Fülber J, Agreste FR, Seidel SRT, Sotelo EDP, Barbosa ÂP, Michelacci YM, Baccarin RYA. Chondrogenic potential of mesenchymal stem cells from horses using a magnetic 3D cell culture system. World J Stem Cells 2021; 13:645-658. [PMID: 34249233 PMCID: PMC8246251 DOI: 10.4252/wjsc.v13.i6.645] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/29/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) represent a promising therapy for the treatment of equine joint diseases, studied due to their possible immunomodulatory characteristics and regenerative capacity. However, the source of most suitable MSCs for producing cartilage for regenerative processes in conjunction with biomaterials for an enhanced function is yet to be established. AIM To compare the chondrogenicity of MSCs derived from synovial fluid, bone marrow, and adipose tissue of horses, using the aggrecan synthesis. METHODS MSCs from ten horses were cultured, phenotypic characterization was done with antibodies CD90, CD44 and CD34 and were differentiated into chondrocytes. The 3D cell culture system in which biocompatible nanoparticles consisting of gold, iron oxide, and poly-L-lysine were added to the cells, and they were forced by magnets to form one microspheroid. The microspheroids were exposed to a commercial culture medium for 4 d, 7 d, 14 d, and 21 d. Proteoglycan extraction was performed, and aggrecan was quantified by enzyme-linked immunosorbent assay. Keratan sulfate and aggrecan in the microspheroids were identified and localized by immunofluorescence. RESULTS All cultured cells showed fibroblast-like appearance, the ability to adhere to the plastic surface, and were positive for CD44 and CD90, thus confirming the characteristics and morphology of MSCs. The soluble protein concentrations were higher in the microspheroids derived from adipose tissue. The aggrecan concentration and the ratio of aggrecan to soluble proteins were higher in microspheroids derived from synovial fluid than in those derived from bone marrow, thereby showing chondrogenic superiority. Microspheroids from all sources expressed aggrecan and keratan sulfate when observed using confocal immunofluorescence microscopy. All sources of MSCs can synthesize aggrecan, however, MSCs from synovial fluid and adipose tissue have demonstrated better biocompatibility in a 3D environment, thus suggesting chondrogenic superiority. CONCLUSION All sources of MSCs produce hyaline cartilage; however, the use of synovial liquid or adipose tissue should be recommended when it is intended for use with biomaterials or scaffolds.
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Affiliation(s)
- Joice Fülber
- Departamento de Clínica Médica, Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo 05506-270, Brazil.
| | - Fernanda R Agreste
- Departamento de Clínica Médica, Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo 05506-270, Brazil
| | - Sarah R T Seidel
- Departamento de Clínica Médica, Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo 05506-270, Brazil
| | - Eric D P Sotelo
- Departamento de Clínica Médica, Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo 05506-270, Brazil
| | - Ângela P Barbosa
- Departamento de Clínica Médica, Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo 05506-270, Brazil
| | - Yara M Michelacci
- Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04044-020, Brazil
| | - Raquel Y A Baccarin
- Departamento de Clínica Médica, Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo 05506-270, Brazil
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Cell-fate decision of mesenchymal stem cells toward osteocyte differentiation is committed by spheroid culture. Sci Rep 2021; 11:13204. [PMID: 34168224 PMCID: PMC8225633 DOI: 10.1038/s41598-021-92607-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 06/14/2021] [Indexed: 01/14/2023] Open
Abstract
Osteocytes are mechanosensory commander cells to regulate bone remodeling throughout the lifespan. While the osteocytes are known as terminally differentiated cells derived from mesenchymal stem cells, the detailed mechanisms of osteocyte differentiation remain unclear. In this study, we fabricated 3D self-organized spheroids using human mesenchymal stem cells (MSCs). Under the osteogenesis induction medium, the spheroid culture model exerted the osteocyte-likeness within 2 days compared to a conventional 2D monolayer model. Moreover, we showed that an inhibition of actin polymerization in the spheroid further up-regulated the osteocyte gene expressions. Notably, we represented that the cell condensed condition acquired in the 3D spheroid culture model determined a differentiation fate of MSCs to osteocytes. Taken together, we suggest that our self-organized spheroid model can be utilized as a new in vitro model to represent the osteocyte and to recapitulate an in vitro ossification process.
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Cai X, Daniels O, Cucchiarini M, Madry H. Ectopic models recapitulating morphological and functional features of articular cartilage. Ann Anat 2021; 237:151721. [PMID: 33753232 DOI: 10.1016/j.aanat.2021.151721] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Articular cartilage is an extremely specialized connective tissue which covers all diarthrodial joints. Implantation of chondrogenic cells without or with additional biomaterial scaffolds in ectopic locationsin vivo generates substitutes of cartilage with structural and functional characteristics that are used in fundamental investigations while also serving as a basis for translational studies. METHODS Literature search in Pubmed. RESULTS AND DISCUSSION This narrative review summarizes the most relevant ectopic models, among which subcutaneous, intramuscular, and kidney capsule transplantation and elaborates on implanted cells and biomaterial scaffolds and on their use to recapitulate morphological and functional features of articular cartilage. Although the absence of a physiological joint environment and biomechanical stimuli is the major limiting factor, ectopic models are an established component for articular cartilage research aiming to generate a bridge between in vitro data and the clinically more relevant translational orthotopic in vivo models when their limitations are considered.
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Affiliation(s)
- Xiaoyu Cai
- Center of Experimental Orthopaedics, Saarland University, Homburg, Germany
| | - Oliver Daniels
- Center of Experimental Orthopaedics, Saarland University, Homburg, Germany
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University, Homburg, Germany
| | - Henning Madry
- Center of Experimental Orthopaedics, Saarland University, Homburg, Germany.
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Brindo da Cruz IC, Velosa APP, Carrasco S, Dos Santos Filho A, Tomaz de Miranda J, Pompeu E, Fernandes TL, Bueno DF, Fanelli C, Goldenstein-Schainberg C, Fabro AT, Fuller R, Silva PL, Capelozzi VL, Teodoro WR. Post-Adipose-Derived Stem Cells (ADSC) Stimulated by Collagen Type V (Col V) Mitigate the Progression of Osteoarthritic Rabbit Articular Cartilage. Front Cell Dev Biol 2021; 9:606890. [PMID: 33829012 PMCID: PMC8019831 DOI: 10.3389/fcell.2021.606890] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 02/22/2021] [Indexed: 12/25/2022] Open
Abstract
Collagen is essential for cartilage adhesion and formation. In the present study, histology, immunofluorescence, morphometry, and qRT-PCR suggested that adipose-derived stem cells (ADSCs) stimulated by type V collagen (Col V) induce a significant increase of type II collagen (Col II) in the degenerative area of surgical-induced osteoarthritic rabbit articular cartilage (OA). In vitro, the effects of Col V on the proliferation and differentiation of ADSC were investigated. The expression of the cartilage-related genes Col2a1 and Acan was significantly upregulated and Pou5fl was downregulated post-ADSC/Col V treatment. Post-ADSC/Col V treatment, in vivo analyses revealed that rabbits showed typical signs of osteoarthritic articular cartilage regeneration by hematoxylin and eosin (H&E) and Safranin O/Fast Green staining. Immunohistochemical staining demonstrated that the volume of Col II fibers and the expression of Col II protein were significantly increased, and apoptosis Fas ligand positive significantly decreased post-ADSC/Col V treatment. In conclusion, the expression of Col II was higher in rabbits with surgical-induced osteoarthritic articular cartilage; hence, ADSC/Col V may be a promising therapeutic target for OA treatment.
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Affiliation(s)
- Isabele Camargo Brindo da Cruz
- Rheumatology Division of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil
| | - Ana Paula Pereira Velosa
- Rheumatology Division of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil
| | - Solange Carrasco
- Rheumatology Division of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil
| | - Antonio Dos Santos Filho
- Rheumatology Division of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil
| | - Jurandir Tomaz de Miranda
- Rheumatology Division of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil
| | - Eduardo Pompeu
- Bioterism Center of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil
| | - Tiago Lazzaretti Fernandes
- Sport Medicine Division, Faculdade de Medicina, Institute of Orthopaedics and Traumatology of the Hospital das Clinicas, Universidade de São Paulo, FMUSP, São Paulo, Brazil.,Hospital Sírio-Libanês, São Paulo, Brazil
| | | | - Camila Fanelli
- Laboratory of Cellular, Genetic and Molecular Nephrology, Renal Division, University of São Paulo, São Paulo, Brazil
| | - Cláudia Goldenstein-Schainberg
- Rheumatology Division of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil
| | - Alexandre Todorovic Fabro
- Department of Pathology of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil.,Respiratory Medicine Laboratory, Department of Pathology and Legal Medicine, Ribeirão Preto Medical School, University of São Paulo (USP), São Paulo, Brazil
| | - Ricardo Fuller
- Rheumatology Division of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil
| | - Pedro Leme Silva
- Laboratory of Pulmonary Investigation, Centro de Ciências da Saúde, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Vera Luiza Capelozzi
- Department of Pathology of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil
| | - Walcy Rosolia Teodoro
- Rheumatology Division of the Hospital das Clinicas, Faculdade de Medicina, Universidade de São Paulo, FMUSP, São Paulo, Brazil
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Promoting Effect of Basic Fibroblast Growth Factor in Synovial Mesenchymal Stem Cell-Based Cartilage Regeneration. Int J Mol Sci 2020; 22:ijms22010300. [PMID: 33396695 PMCID: PMC7796036 DOI: 10.3390/ijms22010300] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/25/2020] [Accepted: 12/25/2020] [Indexed: 01/02/2023] Open
Abstract
Synovial mesenchymal stem cell (SMSC) is the promising cell source of cartilage regeneration but has several issues to overcome such as limited cell proliferation and heterogeneity of cartilage regeneration ability. Previous reports demonstrated that basic fibroblast growth factor (bFGF) can promote proliferation and cartilage differentiation potential of MSCs in vitro, although no reports show its beneficial effect in vivo. The purpose of this study is to investigate the promoting effect of bFGF on cartilage regeneration using human SMSC in vivo. SMSCs were cultured with or without bFGF in a growth medium, and 2 × 105 cells were aggregated to form a synovial pellet. Synovial pellets were implanted into osteochondral defects induced in the femoral trochlea of severe combined immunodeficient mice, and histological evaluation was performed after eight weeks. The presence of implanted SMSCs was confirmed by the observation of human vimentin immunostaining-positive cells. Interestingly, broad lacunae structures and cartilage substrate stained by Safranin-O were observed only in the bFGF (+) group. The bFGF (+) group had significantly higher O’Driscoll scores in the cartilage repair than the bFGF (−) group. The addition of bFGF to SMSC growth culture may be a useful treatment option to promote cartilage regeneration in vivo.
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Kobayashi M, Chijimatsu R, Hart DA, Hamamoto S, Jacob G, Yano F, Saito T, Shimomura K, Ando W, Chung UI, Tanaka S, Yoshikawa H, Nakamura N. Evidence that TD-198946 enhances the chondrogenic potential of human synovium-derived stem cells through the NOTCH3 signaling pathway. J Tissue Eng Regen Med 2020; 15:103-115. [PMID: 33169924 DOI: 10.1002/term.3149] [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: 10/16/2019] [Revised: 11/03/2020] [Accepted: 11/04/2020] [Indexed: 11/10/2022]
Abstract
Human synovium-derived stem cells (hSSCs) are an attractive source of cells for cartilage repair. At present, the quality of tissue and techniques used for cartilage regeneration have scope for improvement. A small compound, TD-198946, was reported to enhance chondrogenic induction from hSSCs; however, other applications of TD-198946, such as priming the cell potential of hSSCs, remain unknown. Our study aimed to examine the effect of TD-198946 pretreatment on hSSCs. HSSCs were cultured with or without TD-198946 for 7 days during expansion culture and then converted into a three-dimensional pellet culture supplemented with bone morphogenetic protein-2 (BMP2) and/or transforming growth factor beta-3 (TGFβ3). Chondrogenesis in cultures was assessed based on the GAG content, histology, and expression levels of chondrogenic marker genes. Cell pellets derived from TD-198946-pretreated hSSCs showed enhanced chondrogenic potential when chondrogenesis was induced by both BMP2 and TGFβ3. Moreover, cartilaginous tissue was efficiently generated from TD-198946-pretreated hSSCs using a combination of BMP2 and TGFβ3. Microarray analysis revealed that NOTCH pathway-related genes and their target genes were significantly upregulated in TD-198946-treated hSSCs, although TD-198946 alone did not upregulate chondrogenesis related markers. The administration of the NOTCH signal inhibitor diminished the effect of TD-198946. Thus, TD-198946 enhances the chondrogenic potential of hSSCs via the NOTCH3 signaling pathway. This study is the first to demonstrate the gradual activation of NOTCH3 signaling during chondrogenesis in hSSCs. The priming of NOTCH3 using TD-198946 provides a novel insight regarding the regulation of the differentiation of hSSCs into chondrocytes.
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Affiliation(s)
- Masato Kobayashi
- Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryota Chijimatsu
- Bone and Cartilage Regenerative Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - David A Hart
- McCaig Institute for Bone and Joint Health, University of Calgary, Calgary, Canada
| | - Shuichi Hamamoto
- Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - George Jacob
- Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Fumiko Yano
- Bone and Cartilage Regenerative Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Taku Saito
- Sensory and Motor System Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Kazunori Shimomura
- Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Wataru Ando
- Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ung-Il Chung
- Center for Disease Biology and Integrative Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Sakae Tanaka
- Sensory and Motor System Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Hideki Yoshikawa
- Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Norimasa Nakamura
- Institute for Medical Science in Sports, Osaka Health Science University, Osaka, Japan
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Kumar A, Ghosh Kadamb A, Ghosh Kadamb K. Mesenchymal or Maintenance Stem Cell & Understanding Their Role in Osteoarthritis of the Knee Joint: A Review Article. THE ARCHIVES OF BONE AND JOINT SURGERY 2020; 8:560-569. [PMID: 33088856 DOI: 10.22038/abjs.2020.42536.2155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Mesenchymal Stem Cell (MSC) therapy in osteoarthritis has been hailed as a promising treatment for osteoarthritis due to their unlimited potential of healing and regeneration. Existing literature regarding their proper name, optimal sources, mechanisms of action, dosage, and route of administration, efficacy, and safety is debatable. This index review article has tried to connect these puzzling pieces of available information and brought clarity on some of these crucial issues. The author believes that Maintenance Stem Cells (MSC) may be a more suitable term than mesenchymal stem cell or medicinal signaling cells as their origin might not be limited to mesodermal tissue. Also, they have been shown capable of self-renewal, differentiation, and maintaining a cascade of healing & possibly regeneration at the implanted site. Only a small percentage of implanted MSC survive and rest undergo apoptosis after releasing growth factors, cytokines, and extracellular vesicles. These surviving MSC become active due to conformational changes induced by anti-environment stimuli and undergo limited self-renewal, proliferation, and differentiation, but only a few of them might incorporate into the host tissues. These cells generate & maintain a momentum of series of regenerative activities to improve the function of joint, stabilize or possibly enhance the cartilage quality. More randomized studies with long term follow-up are required to bring clarity on their ideal source, expansion, culture technique, optimum dosage, and route of administration and long-term safety issues.
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Affiliation(s)
- Ashok Kumar
- Department of Orthopaedics, Saudi German Hospital, Dubai, UAE
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Biological Augmentation of ACL Repair and Reconstruction: Current Status and Future Perspective. Sports Med Arthrosc Rev 2020; 28:49-55. [PMID: 32345926 DOI: 10.1097/jsa.0000000000000266] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Historically, anterior cruciate ligament (ACL) suture repair mostly resulted in failure because of intra-articular hypovascularity and poor intrinsic healing capacity of ACL. ACL reconstruction was therefore deemed the gold standard with a high success rate because of more evolved surgical technique. There are, however, clinical and subclinical disadvantages of reconstruction; low rate in full recovery to sports, donor harvest morbidity, tunnel enlargement, and incomplete microscopic healing of the graft. Recent experimental and clinical studies on biological augmentation of mesenchymal stem cells, platelet-rich plasma, or the other biologic agents with scaffold suggested potential feasibility of positive effects by such bio-therapies for both ACL repair and reconstruction. Biological augmentation of ACL surgery is still in the exploratory stages and more evidence from preclinical and clinical studies is required for implementation in clinical practice.
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40
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Thorup AS, Dell'Accio F, Eldridge SE. Lessons from joint development for cartilage repair in the clinic. Dev Dyn 2020; 250:360-376. [PMID: 32738003 DOI: 10.1002/dvdy.228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/23/2020] [Accepted: 07/24/2020] [Indexed: 12/19/2022] Open
Abstract
More than 250 years ago, William Hunter stated that when cartilage is destroyed it never recovers. In the last 20 years, the understanding of the mechanisms that lead to joint formation and the knowledge that some of these mechanisms are reactivated in the homeostatic responses of cartilage to injury has offered an unprecedented therapeutic opportunity to achieve cartilage regeneration. Very large investments in ambitious clinical trials are finally revealing that, although we do not have perfect medicines yet, disease modification is a feasible possibility for human osteoarthritis.
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Affiliation(s)
- Anne-Sophie Thorup
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Francesco Dell'Accio
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Suzanne E Eldridge
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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41
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Zucchelli E, Birchall M, Bulstrode NW, Ferretti P. Modeling Normal and Pathological Ear Cartilage in vitro Using Somatic Stem Cells in Three-Dimensional Culture. Front Cell Dev Biol 2020; 8:666. [PMID: 32850801 PMCID: PMC7402373 DOI: 10.3389/fcell.2020.00666] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/01/2020] [Indexed: 01/07/2023] Open
Abstract
Microtia (underdeveloped ear) is a rare congenital dysmorphology affecting the development of the outer ear. Although human microtic cartilage has not been fully characterized, chondrogenic cells derived from this tissue have been proposed as a suitable source for autologous auricular reconstruction. The aim of this study was to further characterize native microtic cartilage and investigate the properties of cartilage stem/progenitor cells (CSPCs) derived from it. Two-dimensional (2D) systems are most commonly used to assess the chondrogenic potential of somatic stem cells in vitro, but limit cell interactions and differentiation. Hence here we investigated the behavior of microtic CSPCs in three-dimensional spheroid cultures. Remarkable similarities between human microtic cartilages from five patients, as compared to normal cartilage, were observed notwithstanding possibly different etiologies of the disease. Native microtic cartilage displayed poorly defined perichondrium and hyper-cellularity, an immature phenotype that resembled that of the normal developing human auricular cartilage we studied in parallel. Crucially, our analysis of microtic ears revealed for the first time that, unlike normal cartilage, microtic cartilages are vascularized. Importantly, CSPCs isolated from human microtic and normal ear cartilages were found to recapitulate many characteristics of pathological and healthy tissues, respectively, when allowed to differentiate as spheroids, but not in monolayer cultures. Noteworthily, starting from initially homogeneous cell pellets, CSPC spheroids spontaneously underwent a maturation process in culture, and formed two regions (inner and outer region) separated by a boundary, with distinct cell types that differed in chondrogenic commitment as indicated by expression of chondrogenic markers. Compared to normal ear-derived spheroids, microtic spheroids were asymmetric, hyper-cellularized and the inner and outer regions did not develop properly. Hence, their organization resembled that of native microtic cartilage. Together, our results identify novel features of microtic ears and highlight the importance of 3D self-organizing in vitro systems for better understanding somatic stem cell behavior and disease modeling. Our observations of ear-derived chondrogenic stem cell behavior have implications for choice of cells for tissue engineered reconstructive purposes and for modeling the etiopathogenesis of microtia.
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Affiliation(s)
- Eleonora Zucchelli
- Stem Cells and Regenerative Medicine Section, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Martin Birchall
- UCL Ear Institute, University College London, London, United Kingdom
| | - Neil W. Bulstrode
- Department of Plastic Surgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
| | - Patrizia Ferretti
- Stem Cells and Regenerative Medicine Section, UCL Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
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Dual Network Hydrogels Incorporated with Bone Morphogenic Protein-7-Loaded Hyaluronic Acid Complex Nanoparticles for Inducing Chondrogenic Differentiation of Synovium-Derived Mesenchymal Stem Cells. Pharmaceutics 2020; 12:pharmaceutics12070613. [PMID: 32630047 PMCID: PMC7407334 DOI: 10.3390/pharmaceutics12070613] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/19/2020] [Accepted: 06/26/2020] [Indexed: 01/30/2023] Open
Abstract
Alginate-poloxamer (ALG-POL) copolymer with optimal POL content was synthesized, and it was combined with silk fibroin (SF) for building ALG-POL/SF dual network hydrogels. Hyaluronic acid(HA)/chitosan-poly(dioxanone)(CH-PDO) complex nanoparticles (NPs) with optimized composition and high encapsulation efficiency were employed as a vehicle for loading bone morphogenic protein-7 (BMP-7). BMP-7-loaded HA/CH-PDO NPs were incorporated into ALG-POL/SF hydrogel for constructing composite gels to achieve controlled release of BMP-7. These gels showed thermosensitive sol-gel transitions near physiological temperature and pH; and they were tested to be elastic, tough and strong. Some gels exhibited abilities to administer the BMP-7 release in nearly linear manners for a few weeks. Synovium-derived mesenchymal stem cells (SMSCs) were seeded into optimally fabricated gels for assessing their chondrogenic differentiation potency. Real-time PCR analyses showed that the blank ALG-POL/SF gels were not able to induce the chondrogenic differentiation of SMSCs, whereas SMSCs were detected to significantly express cartilage-related genes once they were seeded in the BMP-7-loaded ALG-POL/SF gel for two weeks. The synthesis of cartilaginous matrix components further confirmed that SMSCs seeded in the BMP-7-loaded ALG-POL/SF gel differentiated toward chondrogenesis. Results suggest that BMP-7-loaded ALG-POL/SF composite gels can function as a promising biomaterial for cartilage tissue engineering applications.
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Ni Z, Zhou S, Li S, Kuang L, Chen H, Luo X, Ouyang J, He M, Du X, Chen L. Exosomes: roles and therapeutic potential in osteoarthritis. Bone Res 2020; 8:25. [PMID: 32596023 PMCID: PMC7305215 DOI: 10.1038/s41413-020-0100-9] [Citation(s) in RCA: 176] [Impact Index Per Article: 35.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/30/2020] [Accepted: 05/09/2020] [Indexed: 12/19/2022] Open
Abstract
Exosomes participate in many physiological and pathological processes by regulating cell-cell communication, which are involved in numerous diseases, including osteoarthritis (OA). Exosomes are detectable in the human articular cavity and were observed to change with OA progression. Several joint cells, including chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and secrete exosomes that influence the biological effects of targeted cells. In addition, exosomes from stem cells can protect the OA joint from damage by promoting cartilage repair, inhibiting synovitis, and mediating subchondral bone remodeling. This review summarizes the roles and therapeutic potential of exosomes in OA and discusses the perspectives and challenges related to exosome-based treatment for OA patients in the future.
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Affiliation(s)
- Zhenhong Ni
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Siru Zhou
- State Key Laboratory of Trauma, Burns and Combined Injury; Medical Cformation of H-type vessel in subchondral enter of Trauma and War Injury; Daping Hospital, Army Medical University of PLA, Chongqing, China
| | - Song Li
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
- Eleven Squadron Three Brigade, School of Basic Medical Science, Army Medical University, Chongqing, China
| | - Liang Kuang
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Hangang Chen
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiaoqing Luo
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Junjie Ouyang
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Mei He
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Xiaolan Du
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
| | - Lin Chen
- Department of Wound Repair and Rehabilitation Medicine, Center of Bone Metabolism and Repair, Laboratory for Prevention and Rehabilitation of Training Injuries, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, China
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Raftery RM, Gonzalez Vazquez AG, Chen G, O'Brien FJ. Activation of the SOX-5, SOX-6, and SOX-9 Trio of Transcription Factors Using a Gene-Activated Scaffold Stimulates Mesenchymal Stromal Cell Chondrogenesis and Inhibits Endochondral Ossification. Adv Healthc Mater 2020; 9:e1901827. [PMID: 32329217 DOI: 10.1002/adhm.201901827] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/18/2020] [Indexed: 02/02/2023]
Abstract
Current treatments for articular cartilage defects relieve symptoms but often only delay cartilage degeneration. Mesenchymal stem cells (MSCs) have shown chondrogenic potential but tend to undergo endochondral ossification when implanted in vivo. Harnessing factors governing joint development to functionalize biomaterial scaffolds, termed developmental engineering, might allow to prime host MSCs to regenerate mature articular cartilage in situ without requiring cell isolation or ex vivo expansion. Therefore, the aim of this study is to develop a gene-activated scaffold capable of delivering developmental cues to host MSCs, thus priming MSCs for articular cartilage differentiation and inhibiting endochondral ossification. It is shown that delivery of the SOX-Trio induced MSCs to over-express COL2A1 and ACAN and deposit a sulfated and collagen type II rich extracellular matrix while hypertrophic gene expression and collagen type X deposition is inhibited. When cell-free SOX-Trio-activated scaffolds are implanted ectopically in vivo, they induced spontaneous chondrogenesis without evidence of hypertrophy. MSCs pre-cultured on SOX-Trio-activated scaffolds prior to implantation differentiate into phenotypically stable chondrocytes as evidenced by a lack of collagen X expression or vascular invasion. This SOX-trio-activated scaffold represents a potent, single treatment, developmentally inspired strategy to prime MSCs in situ for articular cartilage defect repair.
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Affiliation(s)
- Rosanne M. Raftery
- Tissue Engineering Research GroupDepartment of Anatomy and Regenerative MedicineRoyal College of Surgeons in Ireland Dublin D02 YN77 Ireland
- Trinity Centre for Biomedical Engineering (TCBE)Trinity College Dublin Dublin 2 Dublin D02 R590 Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER)RCSI and TCD Dublin D02 YN77 Ireland
| | - Arlyng G. Gonzalez Vazquez
- Tissue Engineering Research GroupDepartment of Anatomy and Regenerative MedicineRoyal College of Surgeons in Ireland Dublin D02 YN77 Ireland
- Trinity Centre for Biomedical Engineering (TCBE)Trinity College Dublin Dublin 2 Dublin D02 R590 Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER)RCSI and TCD Dublin D02 YN77 Ireland
| | - Gang Chen
- Department of Physiology and Medical PhysicsCentre for the Study of Neurological DisordersMicrosurgical Research and Training Facility (MRTF)Royal College of Surgeons in Ireland Dublin D02 YN77 Ireland
| | - Fergal J. O'Brien
- Tissue Engineering Research GroupDepartment of Anatomy and Regenerative MedicineRoyal College of Surgeons in Ireland Dublin D02 YN77 Ireland
- Trinity Centre for Biomedical Engineering (TCBE)Trinity College Dublin Dublin 2 Dublin D02 R590 Ireland
- Advanced Materials and Bioengineering Research Centre (AMBER)RCSI and TCD Dublin D02 YN77 Ireland
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45
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Tissue Engineering and Regenerative Medicine in Craniofacial Reconstruction and Facial Aesthetics. J Craniofac Surg 2020; 31:15-27. [PMID: 31369496 DOI: 10.1097/scs.0000000000005840] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The craniofacial region is anatomically complex and is of critical functional and cosmetic importance, making reconstruction challenging. The limitations of current surgical options highlight the importance of developing new strategies to restore the form, function, and esthetics of missing or damaged soft tissue and skeletal tissue in the face and cranium. Regenerative medicine (RM) is an expanding field which combines the principles of tissue engineering (TE) and self-healing in the regeneration of cells, tissues, and organs, to restore their impaired function. RM offers many advantages over current treatments as tissue can be engineered for specific defects, using an unlimited supply of bioengineered resources, and does not require immunosuppression. In the craniofacial region, TE and RM are being increasingly used in preclinical and clinical studies to reconstruct bone, cartilage, soft tissue, nerves, and blood vessels. This review outlines the current progress that has been made toward the engineering of these tissues for craniofacial reconstruction and facial esthetics.
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Silva JC, Han X, Silva TP, Xia K, Mikael PE, Cabral JMS, Ferreira FC, Linhardt RJ. Glycosaminoglycan remodeling during chondrogenic differentiation of human bone marrow-/synovial-derived mesenchymal stem/stromal cells under normoxia and hypoxia. Glycoconj J 2020; 37:345-360. [PMID: 32086666 DOI: 10.1007/s10719-020-09911-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/20/2020] [Accepted: 01/23/2020] [Indexed: 12/19/2022]
Abstract
Glycosaminoglycans (GAGs) are major components of cartilage extracellular matrix (ECM), which play an important role in tissue homeostasis not only by providing mechanical load resistance, but also as signaling mediators of key cellular processes such as adhesion, migration, proliferation and differentiation. Specific GAG types as well as their disaccharide sulfation patterns can be predictive of the tissue maturation level but also of disease states such as osteoarthritis. In this work, we used a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to perform a comparative study in terms of temporal changes in GAG and disaccharide composition between tissues generated from human bone marrow- and synovial-derived mesenchymal stem/stromal cells (hBMSC/hSMSC) after chondrogenic differentiation under normoxic (21% O2) and hypoxic (5% O2) micromass cultures. The chondrogenic differentiation of hBMSC/hSMSC cultured under different oxygen tensions was assessed through aggregate size measurement, chondrogenic gene expression analysis and histological/immunofluorescence staining in comparison to human chondrocytes. For all the studied conditions, the compositional analysis demonstrated a notable increase in the average relative percentage of chondroitin sulfate (CS), the main GAG in cartilage composition, throughout MSC chondrogenic differentiation. Additionally, hypoxic culture conditions resulted in significantly different average GAG and CS disaccharide percentage compositions compared to the normoxic ones. However, such effect was considerably more evident for hBMSC-derived chondrogenic aggregates. In summary, the GAG profiles described here may provide new insights for the prediction of cartilage tissue differentiation/disease states and to characterize the quality of MSC-generated chondrocytes obtained under different oxygen tension culture conditions.
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Affiliation(s)
- João C Silva
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisbon, Portugal.,Department of Chemistry and Chemical Biology, Biological Sciences, Biomedical Engineering and Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, 12180-3590, USA
| | - Xiaorui Han
- Department of Chemistry and Chemical Biology, Biological Sciences, Biomedical Engineering and Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, 12180-3590, USA
| | - Teresa P Silva
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisbon, Portugal
| | - Ke Xia
- Department of Chemistry and Chemical Biology, Biological Sciences, Biomedical Engineering and Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, 12180-3590, USA
| | - Paiyz E Mikael
- Department of Chemistry and Chemical Biology, Biological Sciences, Biomedical Engineering and Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, 12180-3590, USA
| | - Joaquim M S Cabral
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisbon, Portugal
| | - Frederico Castelo Ferreira
- Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001, Lisbon, Portugal
| | - Robert J Linhardt
- Department of Chemistry and Chemical Biology, Biological Sciences, Biomedical Engineering and Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, 12180-3590, USA.
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Gugjoo MB, Fazili MUR, Gayas MA, Ahmad RA, Dhama K. Animal mesenchymal stem cell research in cartilage regenerative medicine - a review. Vet Q 2020; 39:95-120. [PMID: 31291836 PMCID: PMC8923021 DOI: 10.1080/01652176.2019.1643051] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Healing of articular cartilage is a major clinical challenge as it also lacks a direct vasculature and nerves, and carries a limited number of resident chondrocytes that do not proliferate easily. Damaged articular cartilages are usually replaced by fibrocartilages, which are mechanically and structurally weaker and less resilient. Regenerative medicine involving stem cells is considered to have a definitive potential to overcome the limitations associated with the currently available surgical methods of cartilage repair. Among various stem cell types, mesenchymal stem cells (MSCs) are preferred for clinical applications. These cells can be readily derived from various sources and have the ability to trans-differentiate into various tissue-specific cells, including those of the cartilage by the process of chondrogenesis. Compared to embryonic or induced pluripotent stem cells (iPSCs), no ethical or teratogenic issues are associated with MSCs. These stem cells are being extensively evaluated for the treatment of joint affections and the results appear promising. Unlike human medicine, in veterinary medicine, the literature on stem cell research for cartilage regeneration is limited. This review, therefore, aims to comprehensively discuss the available literature and pinpoint the achievements and limitations associated with the use of MSCs for articular cartilage repair in animal species.
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Affiliation(s)
| | | | | | - Raja Aijaz Ahmad
- Division of Veterinary Clinical Complex, FVSc and AH, SKUAST , Srinagar , India
| | - Kuldeep Dhama
- Division of Pathology, Indian Veterinary Research Institute , Bareilly, India
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Silva JC, Moura CS, Borrecho G, Alves de Matos AP, Cabral JMS, Linhardt RJ, Ferreira FC. Effects of glycosaminoglycan supplementation in the chondrogenic differentiation of bone marrow- and synovial- derived mesenchymal stem/stromal cells on 3D-extruded poly (ε-caprolactone) scaffolds. INT J POLYM MATER PO 2020. [DOI: 10.1080/00914037.2019.1706511] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Affiliation(s)
- João C. Silva
- Department of Bioengineering and iBB, Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
- Department of Chemistry and Chemical Biology, Biological Sciences, Biomedical Engineering and Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Carla S. Moura
- CDRSP – Centre for Rapid and Sustainable Product Development, Polytechnic Institute of Leiria, Rua de Portugal-Zona Industrial, Marinha Grande, Portugal
| | - Gonçalo Borrecho
- Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Quinta da Granja, Caparica, Portugal
| | | | - Joaquim M. S. Cabral
- Department of Bioengineering and iBB, Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Robert J. Linhardt
- Department of Chemistry and Chemical Biology, Biological Sciences, Biomedical Engineering and Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA
| | - Frederico Castelo Ferreira
- Department of Bioengineering and iBB, Institute for Bioengineering and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
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Jacob G, Shimomura K, Krych AJ, Nakamura N. The Meniscus Tear: A Review of Stem Cell Therapies. Cells 2019; 9:E92. [PMID: 31905968 PMCID: PMC7016630 DOI: 10.3390/cells9010092] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/20/2019] [Accepted: 12/28/2019] [Indexed: 02/07/2023] Open
Abstract
Meniscal injuries have posed a challenging problem for many years, especially considering that historically the meniscus was considered to be a structure with no important role in the knee joint. This led to earlier treatments aiming at the removal of the entire structure in a procedure known as a meniscectomy. However, with the current understanding of the function and roles of the meniscus, meniscectomy has been identified to accelerate joint degradation significantly and is no longer a preferred treatment option in meniscal tears. Current therapies are now focused to regenerate, repair, or replace the injured meniscus to restore its native function. Repairs have improved in technique and materials over time, with various implant devices being utilized and developed. More recently, strategies have applied stem cells, tissue engineering, and their combination to potentiate healing to achieve superior quality repair tissue and retard the joint degeneration associated with an injured or inadequately functioning meniscus. Accordingly, the purpose of this current review is to summarize the current available pre-clinical and clinical literature using stem cells and tissue engineering for meniscal repair and regeneration.
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Affiliation(s)
- George Jacob
- Department and Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (G.J.); (K.S.)
| | - Kazunori Shimomura
- Department and Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan; (G.J.); (K.S.)
| | - Aaron J. Krych
- Department of Orthopaedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Norimasa Nakamura
- Institute for Medical Science in Sports, Osaka Health Science University, Osaka 530-0043, Japan
- Global Centre for Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan
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Mantripragada VP, Piuzzi NS, Bova WA, Boehm C, Obuchowski NA, Lefebvre V, Midura RJ, Muschler GF. Donor-matched comparison of chondrogenic progenitors resident in human infrapatellar fat pad, synovium, and periosteum - implications for cartilage repair. Connect Tissue Res 2019; 60:597-610. [PMID: 31020864 DOI: 10.1080/03008207.2019.1611795] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Purpose: There is a clinical need to better characterize tissue sources being used for stem cell therapies. This study focuses on comparison of cells and connective tissue progenitors (CTPs) derived from native human infrapatellar fatpad (IPFP), synovium (SYN), and periosteum (PERI). Materials and Methods: IPFP, SYN, PERI were harvested from twenty-eight patients undergoing arthroplasty. CTPs were quantitatively characterized using automated colony-forming-unit assay to compare total nucleated cell concentration-[Cell], cells/mg; prevalence-(PCTP), CTPs/million nucleated cells; CTP concentration-[CTP], CTPs/mg; proliferation and differentiation potential; and correlate outcomes with patient's age and gender. Results: [Cell] did not differ between IPFP, SYN, and PERI. PCTP was influenced by age and gender: patients >60 years, IPFP and SYN had higher PCTP than PERI (p < 0.001) and females had higher PCTP in IPFP (p < 0.001) and SYN (p = 0.001) than PERI. [CTP] was influenced by age: patients <50 years, SYN (p = 0.0165) and PERI (p < 0.001) had higher [CTP] than IPFP; patients between 60 and 69 years, SYN (p < 0.001) had higher [CTP] than PERI; patients >70 years, IPFP (p = 0.006) had higher [CTP] than PERI. In patients >60 years, proliferation potential of CTPs differed significantly (SYN>IPFP>PERI); however, differentiation potentials were comparable between all three tissue sources. Conclusion: SYN and IPFP may serve as a preferred tissue source for patients >60 years, and PERI along with SYN and IPFP may serve as a preferred tissue source for patients <60 years for cartilage repair. However, the heterogeneity among the CTPs in any given tissue source suggests performance-based selection might be useful to optimize cell-sourcing strategies to improve efficacy of cellular therapies for cartilage repair.
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Affiliation(s)
- V P Mantripragada
- Department of Biomedical Engineering, Lerner Research Institute , Cleveland , OH , USA
| | - N S Piuzzi
- Department of Biomedical Engineering, Lerner Research Institute , Cleveland , OH , USA.,Department of Orthopedic Surgery, Cleveland Clinic , Cleveland , OH , USA.,Department of Orthopaedic Surgery, Instituto Universitario del Hospital Italiano de Buenos Aires , Buenos Aires , Argentina
| | - W A Bova
- Department of Biomedical Engineering, Lerner Research Institute , Cleveland , OH , USA
| | - C Boehm
- Department of Biomedical Engineering, Lerner Research Institute , Cleveland , OH , USA
| | - N A Obuchowski
- Department of Quantitative Health Science, Cleveland Clinic , Cleveland , OH , USA
| | - V Lefebvre
- Department of Cellular and Molecular Medicine, Cleveland Clinic , Cleveland , OH , USA
| | - R J Midura
- Department of Biomedical Engineering, Lerner Research Institute , Cleveland , OH , USA
| | - G F Muschler
- Department of Biomedical Engineering, Lerner Research Institute , Cleveland , OH , USA.,Department of Orthopedic Surgery, Cleveland Clinic , Cleveland , OH , USA
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