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Wang JY, Liu YH, Wang X, Ma M, Pan ZY, Fan AY, Lu LY, Liu Z, Tao K, Yin F. Atf3 + senescent chondrocytes mediate meniscus degeneration in aging. Arthritis Res Ther 2025; 27:105. [PMID: 40375324 PMCID: PMC12082910 DOI: 10.1186/s13075-025-03566-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 05/02/2025] [Indexed: 05/18/2025] Open
Abstract
BACKGROUND Meniscus degeneration contributes to knee arthritis progression, but the cellular and molecular mechanisms of meniscus aging remain poorly understood. We aimed to characterize age-related changes in the rat meniscus using single-cell RNA sequencing (scRNA-seq) and identify key pathogenic cell populations and pathways. METHODS Meniscal tissues from young (12 weeks) and aged (24 months) rats were processed for histology, flow cytometry, and scRNA-seq. Bioinformatics tools, including Seurat, Monocle 2, and CellChat, were used to analyze cellular composition, pseudotime trajectories, and intercellular communication. Senescence-related features and signaling pathways were evaluated. RESULTS Knee joint of aged rats exhibited higher Osteoarthritis Research Society International (OARSI) scores and synovial inflammation. scRNA-seq revealed three major chondrocyte subpopulations: Sox9 + stable chondrocytes, Fndc1 + fibrochondrocytes, and Atf3 + senescent chondrocytes. Aging caused a significant increase in Atf3 + senescent chondrocytes, characterized by the expression of senescence markers (Cdkn1a/Cdkn2a) and activation of inflammatory pathways such as tumor necrosis factor (TNF) and nuclear factor-κB (NF-κB). These cells were predominantly located at the endpoint of differentiation trajectories. CellChat analysis identified the ANGPTL4-SDC4 axis as a key signaling pathway mediated by Atf3 + cells. Immunostaining confirmed elevated Angiopoietin-Like Protein 4 (ANGPTL4) expression in aged menisci. CONCLUSION We identified Atf3 + senescent chondrocytes as a key pathogenic population in the aging meniscus, driving degeneration via the ANGPTL4 pathway. Targeting Atf3 + cells or ANGPTL4 signaling may offer new therapeutic strategies for age-related meniscus degeneration and arthritis.
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Affiliation(s)
- Jing-Yi Wang
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Yao-Hui Liu
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Xiao Wang
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Min Ma
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Zhang-Yi Pan
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Ao-Yuan Fan
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Lai-Ya Lu
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Zheng Liu
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Kun Tao
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
- Department of Joint Surgery, Ningbo No.6 Hospital, Ningbo, Zhejiang, China.
| | - Feng Yin
- Department of Joint Surgery, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China.
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Zheng C, Wu Y, Luan F, Wei C, Zhang C, Liu W, Wang W, Chen J. Advances in biomimetic hydrogel for articular cartilage defect repair: Enabling immunomodulation and chondrogenesis. Colloids Surf B Biointerfaces 2025; 253:114760. [PMID: 40359898 DOI: 10.1016/j.colsurfb.2025.114760] [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: 02/19/2025] [Revised: 04/22/2025] [Accepted: 05/02/2025] [Indexed: 05/15/2025]
Abstract
Articular cartilage defects, as a core pathologic feature in the progression of osteoarthritis, and their irreversible degenerative changes lead to functional impairment and socioeconomic burden for tens of millions of patients worldwide. Hydrogels have become key biomaterials in cartilage regeneration with the three-dimensional network structure, programmable mechanical properties, and cell-adaptive microenvironment of biomimetic extracellular matrix. In recent years, several hydrogel systems with in vitro/in vivo repair potential have been developed by modulating the material topology, dynamic mechanical response, and delivery of bioactive factors, and some of them have entered the clinical translation stage. This review systematically explains the biomimetic design principles of hydrogels. It analyzes the immunomodulation and chondrogenic mechanisms mediated by hydrogels, providing a theoretical framework for the development of next-generation smart cartilage repair materials.
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Affiliation(s)
- Chenxiao Zheng
- Department ofOrthopaedics and Traumatology, Zhongshan Hospital of Traditional ChineseMedicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, Guangdong 528401, China
| | - Yurui Wu
- Department ofOrthopaedics and Traumatology, Zhongshan Hospital of Traditional ChineseMedicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, Guangdong 528401, China
| | - Feifan Luan
- Department ofOrthopaedics and Traumatology, Zhongshan Hospital of Traditional ChineseMedicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, Guangdong 528401, China
| | - Chunwei Wei
- Department ofOrthopaedics and Traumatology, Zhongshan Hospital of Traditional ChineseMedicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, Guangdong 528401, China
| | - Chunye Zhang
- Biomedical and HealthTechnology Innovation Platform, National University of Singapore (Suzhou)Research Institute, Suzhou, Jiangsu 215123, China
| | - Wenjun Liu
- Zhejiang ShangyueBiotechnology Research Center, Hangzhou, Zhejiang 310018, China
| | - Wenjun Wang
- Biomedical and HealthTechnology Innovation Platform, National University of Singapore (Suzhou)Research Institute, Suzhou, Jiangsu 215123, China.
| | - Jiayi Chen
- Department ofOrthopaedics and Traumatology, Zhongshan Hospital of Traditional ChineseMedicine Affiliated to Guangzhou University of Chinese Medicine, Zhongshan, Guangdong 528401, China.
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Kuczyński N, Boś J, Białoskórska K, Aleksandrowicz Z, Turoń B, Zabrzyńska M, Bonowicz K, Gagat M. The Meniscus: Basic Science and Therapeutic Approaches. J Clin Med 2025; 14:2020. [PMID: 40142829 PMCID: PMC11942698 DOI: 10.3390/jcm14062020] [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: 02/17/2025] [Revised: 03/10/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
The proper function and longevity of the knee joint are ensured by the knee menisci. Their susceptibility to damage and injury is one of the main risk factors for rapid cartilage loss and the development of osteoarthritis. The vascularization pattern and nutritional status of a torn meniscus determine its potential for healing and the success of meniscus surgery. Blood supply is a crucial factor in assessing healing potential. Knee cartilage volume loss and its modification often result from meniscal damage or excision, leading to osteoarthritis. Modern methods for preserving meniscal tissue are currently the treatment of choice. Magnetic resonance imaging (MRI) is the gold standard for assessing meniscus lesions. It provides a comprehensive evaluation of tear stability and progression risk. Additionally, it offers high sensitivity and specificity. Arthrography combined with computed tomography (CT) can be used for patients who are unable to undergo MRI. Other methods, such as X-ray and ultrasound, are not useful for the typical diagnosis of meniscal lesions. Minimally invasive surgery has become the gold standard for both treatment and diagnosis. Modern techniques, such as all-inside compression sutures and other suturing techniques, are also considered. In contrast, in the past, open total meniscectomy was routinely performed as the gold standard, based on the mistaken belief that the menisci were functionless. Currently, new treatment methods for meniscal lesions are being explored, including mesenchymal stem cells, synthetic implants, and platelet-rich plasma (PRP). The crucial role of the menisci in knee biomechanics drives the development of modern solutions focused on preserving meniscal tissue.
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Affiliation(s)
- Nikodem Kuczyński
- Department of Morphological and Physiological Sciences, Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, 09-402 Płock, Poland; (N.K.); (J.B.); (K.B.); (Z.A.); (K.B.)
| | - Julia Boś
- Department of Morphological and Physiological Sciences, Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, 09-402 Płock, Poland; (N.K.); (J.B.); (K.B.); (Z.A.); (K.B.)
| | - Kinga Białoskórska
- Department of Morphological and Physiological Sciences, Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, 09-402 Płock, Poland; (N.K.); (J.B.); (K.B.); (Z.A.); (K.B.)
| | - Zuzanna Aleksandrowicz
- Department of Morphological and Physiological Sciences, Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, 09-402 Płock, Poland; (N.K.); (J.B.); (K.B.); (Z.A.); (K.B.)
| | - Bartosz Turoń
- Department of Trauma and Orthopedics, Regional Specialist Hospital in Grudziądz, 86-300 Grudziądz, Poland;
| | - Maria Zabrzyńska
- Department of Family Medicine, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-094 Bydgoszcz, Poland;
| | - Klaudia Bonowicz
- Department of Morphological and Physiological Sciences, Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, 09-402 Płock, Poland; (N.K.); (J.B.); (K.B.); (Z.A.); (K.B.)
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-092 Bydgoszcz, Poland
| | - Maciej Gagat
- Department of Morphological and Physiological Sciences, Faculty of Medicine, Collegium Medicum, Mazovian Academy in Płock, 09-402 Płock, Poland; (N.K.); (J.B.); (K.B.); (Z.A.); (K.B.)
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 85-092 Bydgoszcz, Poland
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Yan WT, Wang JS, Fan PZ, Roberts S, Wright K, Zhang ZZ. The clinical potential of meniscal progenitor cells. THE JOURNAL OF CARTILAGE & JOINT PRESERVATION 2024; 4:None. [PMID: 39669533 PMCID: PMC11636529 DOI: 10.1016/j.jcjp.2024.100166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/29/2024] [Accepted: 02/11/2024] [Indexed: 12/14/2024]
Abstract
Introduction The meniscus is an important cushioning structure of the knee joint, with the maintenance of its normal structure and function playing a crucial role in protecting the joint from early degeneration. Stem/progenitor cells could be the key to help researchers to have a deeper understanding of the biological process of meniscal injury repair and may be important in the meniscus tissue regeneration processes. To the best of our knowledge, there is currently a lack of comprehensive reviews on existing research about the meniscus progenitor cells (MPCs). Objectives By reviewing the existing MPC literature, we aim to provide insights for future research on meniscus regeneration. Methods The isolation methods, biological characteristics and the translational application of MPCs were summarized. Results MPCs could be isolated according to their colony-forming ability, marker expression, migration ability, and differential adhesion to fibronectin. Most existing studies on surface markers of MPCs have largely followed the paradigm of mesenchymal stromal/stem cell research. Based on the information provided by their surface markers and expression profile, researchers located MPCs in the peripheral surface area of the meniscus. Few researches have investigated the translation and application of MPCs, with most studies being limited to MPCs extraction and subsequent reimplantation in vivo. Conclusions MPCs are a group of meniscus-resident cells, which exhibit certain stem/progenitor cell characteristics, such as the ability to undergo multilineage differentiation in in vitro culture.
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Affiliation(s)
- Wan-Ting Yan
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jing-Song Wang
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | | | - Sally Roberts
- Spinal Studies & Cartilage Research Group, Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry, United Kingdom
- School of Pharmacy and Bioengineering, Keele University, Staffordshire, United Kingdom
| | - Karina Wright
- Spinal Studies & Cartilage Research Group, Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust, Oswestry, United Kingdom
- School of Pharmacy and Bioengineering, Keele University, Staffordshire, United Kingdom
| | - Zheng-Zheng Zhang
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
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Fuchioka Y, Endo K, Sakamaki Y, Tanimoto T, Ozeki N, Nakagawa Y, Koga H, Tomita M, Sekiya I. Scanning electron microscopy analysis of synovial and adipose mesenchymal stem cells adhering to cartilage. Regen Ther 2024; 27:488-495. [PMID: 38756702 PMCID: PMC11096720 DOI: 10.1016/j.reth.2024.04.012] [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: 01/25/2024] [Revised: 03/30/2024] [Accepted: 04/25/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction Mesenchymal stem cells (MSCs) are increasingly used for intra-articular injections in the treatment of knee osteoarthritis. The aim of this study was to use scanning electron microscopy (SEM) to compare the morphological characteristics of synovial and adipose MSCs. Methods Synovium and adipose tissues were concurrently harvested from eight patients with knee osteoarthritis. Suspensions of both synovial and adipose MSCs were examined to identify the presence of microspikes. In addition to this study, the MSC suspensions in four patients were applied to abraded porcine cartilage discs and observed 10 s, 10 min, and 1 h later. Results The median percentage of cells exhibiting microspikes was 14% for synovial MSC suspensions and 13% for adipose MSC suspensions; this difference was not statistically significant (n = 8). No notable differences were detected in the number of adherent cells or in the proportion of cells displaying microspikes or pseudopodia. Strong correlations were found between the proportion of cells with pseudopodia and the number of attached cells for both synovial (r = 0.92, n = 12) and adipose (r = 0.86, n = 12) MSCs, with no significant difference in the correlation coefficients between the two groups. Conclusion SEM analysis revealed no obvious differences in morphological characteristics during MSC adhesion to cartilage for either synovial or adipose MSCs.
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Affiliation(s)
- Yusuke Fuchioka
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kentaro Endo
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuriko Sakamaki
- Research Core, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takahiro Tanimoto
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Nobutake Ozeki
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yusuke Nakagawa
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Makoto Tomita
- School of Data Science, Graduate School of Data Science, Yokohama City University, Kanagawa, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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Monfort-Ferré D, Boronat-Toscano A, Sánchez-Herrero JF, Caro A, Menacho M, Vañó-Segarra I, Martí M, Espina B, Pluvinet R, Cabrinety L, Abadia C, Ejarque M, Nuñez-Roa C, Maymo-Masip E, Sumoy L, Vendrell J, Fernández-Veledo S, Serena C. Genome-wide DNA Methylome and Transcriptome Profiling Reveals Key Genes Involved in the Dysregulation of Adipose Stem Cells in Crohn's Disease. J Crohns Colitis 2024; 18:1644-1659. [PMID: 38747506 DOI: 10.1093/ecco-jcc/jjae072] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 04/18/2024] [Accepted: 05/13/2024] [Indexed: 10/17/2024]
Abstract
BACKGROUND AND AIMS Crohn's disease [CD] is characterised by the expansion of mesenteric adipose tissue [MAT], named creeping fat [CF], which seems to be directly related to disease activity. Adipose-stem cells [ASCs] isolated from the CF of patients with CD are extremely pro-inflammatory, which persists during disease remission. We hypothesised that the dysfunctional ASCs in CD accumulate epigenetic modifications triggered by the inflammatory environment, that could serve as molecular markers. METHODS Genome-wide DNA methylome and transcriptome profiling were performed in ASCs isolated from MAT biopsies of patients with active and inactive disease and from non-Crohn's disease patients [non-CD]. A validation cohort was used to test the main candidate genes via quantitative polymerase chain reaction in other fat depots and immune cells. RESULTS We found differences in DNA methylation and gene expression between ASCs isolated from patients with CD and from non-CD subjects, but we found no differences related to disease activity. Pathway enrichment analysis revealed that oxidative stress and immune response were significantly enriched in active CD, and integration analysis identified MAB21L2, a cell fate-determining gene, as the most affected gene in CD. Validation analysis confirmed the elevated gene expression of MAB21L2 in MAT and in adipose tissue macrophages in active CD. We also found a strong association between expression of the calcium channel subunit gene CACNA1H and disease remission, as CACNA1H expression was higher in ASCs and MAT from patients with inactive CD, and correlates negatively with C-reactive protein in peripheral blood mononuclear cells. CONCLUSION We identified a potential gene signature of CD in ASCs obtained from MAT. Integration analysis highlighted two novel genes demonstrating a negative correlation between promoter DNA methylation and transcription: one linked to ASCs in CD [MAB21L2] and the other [CACNA1H] related to disease remission.
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Affiliation(s)
- Diandra Monfort-Ferré
- Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
| | - Albert Boronat-Toscano
- Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
| | | | - Aleidis Caro
- Unitat de Cirurgia Colorectal, Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain
| | - Margarita Menacho
- Servei de Digestiu, Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain
| | - Irene Vañó-Segarra
- Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
| | - Marc Martí
- Unitat de Cirurgia Colorectal, Servei de Cirurgia General, Hospital Vall d'Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Beatriz Espina
- Unitat de Cirurgia Colorectal, Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain
| | - Raquel Pluvinet
- Genòmica d'Alt Contingut i Bioinformàtica, Institut d'Investigació Germans Trias i Pujol, Badalona, Spain
- Unitat de Genòmica, Josep Carreras Leukaemia Research Institute, Badalona, Spain
| | - Lidia Cabrinety
- Servei de Digestiu, Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain
| | - Carme Abadia
- Servei de Digestiu, Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Tarragona, Spain
| | - Miriam Ejarque
- Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
| | - Cati Nuñez-Roa
- Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
| | - Elsa Maymo-Masip
- Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud, Carlos III, Madrid, Spain
| | - Lauro Sumoy
- Genòmica d'Alt Contingut i Bioinformàtica, Institut d'Investigació Germans Trias i Pujol, Badalona, Spain
| | - Joan Vendrell
- Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud, Carlos III, Madrid, Spain
| | - Sonia Fernández-Veledo
- Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud, Carlos III, Madrid, Spain
| | - Carolina Serena
- Hospital Universitari Joan XXIII, Institut d´Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, Tarragona, Spain
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Zhang Y, Chen J, Sun Y, Wang M, Liu H, Zhang W. Endogenous Tissue Engineering for Chondral and Osteochondral Regeneration: Strategies and Mechanisms. ACS Biomater Sci Eng 2024; 10:4716-4739. [PMID: 39091217 DOI: 10.1021/acsbiomaterials.4c00603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Increasing attention has been paid to the development of effective strategies for articular cartilage (AC) and osteochondral (OC) regeneration due to their limited self-reparative capacities and the shortage of timely and appropriate clinical treatments. Traditional cell-dependent tissue engineering faces various challenges such as restricted cell sources, phenotypic alterations, and immune rejection. In contrast, endogenous tissue engineering represents a promising alternative, leveraging acellular biomaterials to guide endogenous cells to the injury site and stimulate their intrinsic regenerative potential. This review provides a comprehensive overview of recent advancements in endogenous tissue engineering strategies for AC and OC regeneration, with a focus on the tissue engineering triad comprising endogenous stem/progenitor cells (ESPCs), scaffolds, and biomolecules. Multiple types of ESPCs present within the AC and OC microenvironment, including bone marrow-derived mesenchymal stem cells (BMSCs), adipose-derived mesenchymal stem cells (AD-MSCs), synovial membrane-derived mesenchymal stem cells (SM-MSCs), and AC-derived stem/progenitor cells (CSPCs), exhibit the ability to migrate toward injury sites and demonstrate pro-regenerative properties. The fabrication and characteristics of scaffolds in various formats including hydrogels, porous sponges, electrospun fibers, particles, films, multilayer scaffolds, bioceramics, and bioglass, highlighting their suitability for AC and OC repair, are systemically summarized. Furthermore, the review emphasizes the pivotal role of biomolecules in facilitating ESPCs migration, adhesion, chondrogenesis, osteogenesis, as well as regulating inflammation, aging, and hypertrophy-critical processes for endogenous AC and OC regeneration. Insights into the applications of endogenous tissue engineering strategies for in vivo AC and OC regeneration are provided along with a discussion on future perspectives to enhance regenerative outcomes.
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Affiliation(s)
- Yanan Zhang
- School of Medicine, Southeast University, 210009 Nanjing, China
| | - Jialin Chen
- School of Medicine, Southeast University, 210009 Nanjing, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, 210096 Nanjing, China
- China Orthopedic Regenerative Medicine Group (CORMed), 310058 Hangzhou, China
| | - Yuzhi Sun
- Department of Orthopaedic Surgery, Institute of Digital Medicine, Nanjing First Hospital, Nanjing Medical University, 210006 Nanjing, China
| | - Mingyue Wang
- School of Medicine, Southeast University, 210009 Nanjing, China
| | - Haoyang Liu
- School of Medicine, Southeast University, 210009 Nanjing, China
| | - Wei Zhang
- School of Medicine, Southeast University, 210009 Nanjing, China
- Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, 210096 Nanjing, China
- China Orthopedic Regenerative Medicine Group (CORMed), 310058 Hangzhou, China
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Yan WT, Wang JS, Guo SY, Zhu JH, Zhang ZZ. Isolation and Characterization of Meniscus Progenitor Cells From Rat, Rabbit, Goat, and Human. Cartilage 2024:19476035241266579. [PMID: 39058020 PMCID: PMC11569696 DOI: 10.1177/19476035241266579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 04/22/2024] [Accepted: 06/20/2024] [Indexed: 07/28/2024] Open
Abstract
OBJECTIVE Meniscus progenitor cells (MPCs) have been identified as promising candidates for meniscus regeneration, and it is crucial for us to understand meniscus injury repair mechanism at the cellular level. In this study, we investigate the biological properties of MPCs isolated from different species using the differential adhesion to fibronectin (DAF) technique. We aim to characterize MPCs in different species and evaluate the feasibility of these models for future meniscal investigation. DESIGN MPCs were isolated from freshly digested meniscus from rat, rabbit, goat, and human cells using DAF. Biological properties, including proliferation, colony-forming, multilineage differentiation, and migration abilities, were compared in MPCs and their corresponding mixed meniscus cell (MCs) population in each species. RESULTS MPCs were successfully isolated by the DAF technique in all species. Rat MPCs appeared cobblestone-like, rabbit MPCs were more polygonal, goat MPCs had a spindle-shaped morphology, human MPCs appear more fibroblast-like. Compared with MCs, isolated MPCs showed progenitor cell characteristics, including multilineage differentiation ability and MSC (mesenchymal stem cells) markers (CD166, CD90, CD44, Stro-1) expression. They also highly expressed fibronectin receptors CD49e and CD49c. MPCs also showed greater proliferation capacity and retained colony-forming ability. Except for goat MPCs showed greater migration abilities than MCs, no significant differences were found in the migration ability between MPCs and MCs in other species. CONCLUSION Our study shows that DAF is an effective method for isolating MPCs from rat, rabbit, goat, and human. MPCs in these species demonstrated similar characteristics, including greater proliferation ability and better chondrogenic potential.
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Affiliation(s)
- Wan-Ting Yan
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Jing-Song Wang
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Shu-Yang Guo
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Jia-Hao Zhu
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
| | - Zheng-Zheng Zhang
- Department of Sports Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P.R. China
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Oyama S, Kanamoto T, Ebina K, Etani Y, Hirao M, Goshima A, Otani S, Hikida M, Yamakawa S, Ito S, Okada S, Nakata K. Cyclic compressive loading induces a mature meniscal cell phenotype in mesenchymal stem cells with an atelocollagen-based scaffold. Front Bioeng Biotechnol 2024; 12:1394093. [PMID: 38832131 PMCID: PMC11145507 DOI: 10.3389/fbioe.2024.1394093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 04/24/2024] [Indexed: 06/05/2024] Open
Abstract
Introduction: Biomechanical stimulation is reportedly pivotal in meniscal regeneration, although its effect on mesenchymal stem cell (MSC) meniscal differentiation remains elusive. In this study, we investigated how cyclic compressive loading (CCL) could impact MSCs using three-dimensional cultures in atelocollagen-based meniscal substitute (ACMS). Methods: We extracted MSCs from the meniscus, synovium, and articular cartilage, cultured them in three-dimensional cultures, and exposed them to CCL for 7 days. We then compared the transcriptomes of MSCs treated with and without CCL. Results: Our RNA-seq analysis revealed that CCL induced significant transcriptome changes, significantly affecting chondrocyte-related genes, including SOX9, TGFB1, and PRG4 upregulation. CCL induced transcriptional differentiation of meniscus progenitors toward mature meniscal cells. Conclusion: This study unveils the potential of mechanical stress in promoting MSC meniscal differentiation within ACMS. Our investigations provide new insights for mechanisms underlying meniscal regeneration with ACMS.
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Affiliation(s)
- Shohei Oyama
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
- Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Takashi Kanamoto
- Department of Medicine for Sports and Performing Arts, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kosuke Ebina
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuki Etani
- Department of Medicine for Sports and Performing Arts, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Makoto Hirao
- Department of Orthopaedic Surgery, National Hospital Organization, Osaka Minami Medical Center, Osaka, Japan
| | - Atsushi Goshima
- Department of Orthopaedic Surgery, Osaka Rosai Hospital, Osaka, Japan
| | - Shunya Otani
- Department of Medicine for Sports and Performing Arts, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Minami Hikida
- Department of Medicine for Sports and Performing Arts, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Yamakawa
- Department of Sports Medical Biomechanics, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Shohei Ito
- Taisho Pharmaceutical Co., Ltd., Saitama, Japan
| | - Seiji Okada
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ken Nakata
- Department of Medicine for Sports and Performing Arts, Osaka University Graduate School of Medicine, Osaka, Japan
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10
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Anz AW, Cook JJ, Branch EA, Rahming CA, Ostrander RV, Jordan SE. Cells Remain Viable When Collected With an In-Line-Suction Tissue Collector From Byproducts of Anterior Cruciate Ligament Reconstruction Surgery. Arthrosc Sports Med Rehabil 2024; 6:100860. [PMID: 38293244 PMCID: PMC10827406 DOI: 10.1016/j.asmr.2023.100860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 12/04/2023] [Indexed: 02/01/2024] Open
Abstract
Purpose To investigate the viability of cells collected with an in-line-suction autologous tissue collector from the tissue byproducts of arthroscopic anterior cruciate ligament (ACL) reconstruction, to characterize cells from different tissue types, and to identify mesenchymal stem cells. Methods Patients aged 14 to 50 years with ACL injuries requiring arthroscopic reconstruction surgery were offered enrollment and screened for participation. In total, 12 patients were enrolled in the descriptive laboratory study. Arthroscopic byproduct tissue was collected with an in-line-suction autologous tissue collector from 4 intraoperative collection sites for each patient: ACL stump, ACL fat pad, notchplasty debris, and tunnel drilling debris. All tissue samples were digested using collagenase, and the derived cellular populations were analyzed in vitro, characterizing cellular viability, proliferative potential, qualitative multipotent differentiation capacity, and cell-surface marker presence. Results An equivalent mass of arthroscopic byproduct tissue was taken from each of the 4 intraoperative collection sites (1.12-1.61 g, P = .433), which all showed an average viability of at least 99.95% and high average total nucleated cells (≥1.37 × 107 cells/mL). No significant differences in collected mass (P = .433), cellular viability (P = .880), or total nucleated cells (P = .692) were observed between the 4 byproduct tissues. The byproduct tissues did exhibit significant differences in monocyte (P = .037) and red blood cell (P = .038) concentrations, specifically with greater values present in the ACL stump tissue. Cells from all byproduct tissues adhered to plastic cell culture flasks. Significant differences were found between colony-forming unit fibroblast counts of the 4 byproduct tissues when plated at 106 (P = .003) and 103 (P = .016) cells as the initial seeding density. There was a significant relationship found between both the starting concentration (χ2 = 32.7, P < .001) and the byproduct tissue type (χ2 = 30.4, P < .001) to the presence of ≥80% confluency status at 10 days. Cells obtained from all 4 byproduct tissues qualitatively showed positive tri-lineage (adipocyte, osteoblast, chondroblast) differentiation potential compared with negative controls under standardized in vitro differentiation conditions. Cells derived from all 4 byproduct tissues expressed cell-surface antigens CD105+, CD73+, CD90+, CD45-, CD14-, and CD19- (>75%), and did not express CD45 (<10%). There were no statistically significant differences in cell-surface antigens between the four byproduct tissues. Conclusions This descriptive laboratory study demonstrated that cells derived from arthroscopic byproduct tissues of ACL reconstruction remain viable when collected with an in-line-suction autologous tissue collector and these cells meet the ISCT criteria to qualify as mesenchymal stem cells. Clinical Relevance It is known that viable mesenchymal stem cells reside in byproduct tissue of anterior cruciate ligament reconstruction surgery (ACLR). Practical methods to harvest these cells at the point of care require further development. This study validates the use of an in-line-suction autologous tissue collector for the harvest of viable mesenchymal stem cells after ACLR.
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Affiliation(s)
- Adam W. Anz
- Andrews Institute Center for Regenerative Medicine, Department of Research, Andrews Research & Education Foundation (AREF), Gulf Breeze, Florida, U.S.A
| | - Joshua J. Cook
- Andrews Institute Center for Regenerative Medicine, Department of Research, Andrews Research & Education Foundation (AREF), Gulf Breeze, Florida, U.S.A
| | - Eric A. Branch
- Andrews Institute Center for Regenerative Medicine, Department of Research, Andrews Research & Education Foundation (AREF), Gulf Breeze, Florida, U.S.A
| | - Charlkesha A. Rahming
- Andrews Institute Center for Regenerative Medicine, Department of Research, Andrews Research & Education Foundation (AREF), Gulf Breeze, Florida, U.S.A
| | - Roger V. Ostrander
- Andrews Institute Center for Regenerative Medicine, Department of Research, Andrews Research & Education Foundation (AREF), Gulf Breeze, Florida, U.S.A
| | - Steve E. Jordan
- Andrews Institute Center for Regenerative Medicine, Department of Research, Andrews Research & Education Foundation (AREF), Gulf Breeze, Florida, U.S.A
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11
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Review of Basic Research about Ossification of the Spinal Ligaments Focusing on Animal Models. J Clin Med 2023; 12:jcm12051958. [PMID: 36902744 PMCID: PMC10003841 DOI: 10.3390/jcm12051958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/25/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Ossification of the posterior longitudinal ligament (OPLL) is a heterotopic ossification that may cause spinal cord compression. With the recent development of computed tomography (CT) imaging, it is known that patients with OPLL often have complications related to ossification of other spinal ligaments, and OPLL is now considered part of ossification of the spinal ligaments (OSL). OSL is known to be a multifactorial disease with associated genetic and environmental factors, but its pathophysiology has not been clearly elucidated. To elucidate the pathophysiology of OSL and develop novel therapeutic strategies, clinically relevant and validated animal models are needed. In this review, we focus on animal models that have been reported to date and discuss their pathophysiology and clinical relevance. The purpose of this review is to summarize the usefulness and problems of existing animal models and to help further the development of basic research on OSL.
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12
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Nagai H, Miwa A, Yoneda K, Fujisawa K, Takami T. Optimizing the Seeding Density of Human Mononuclear Cells to Improve the Purity of Highly Proliferative Mesenchymal Stem Cells. BIOENGINEERING (BASEL, SWITZERLAND) 2023; 10:bioengineering10010102. [PMID: 36671674 PMCID: PMC9855129 DOI: 10.3390/bioengineering10010102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 12/29/2022] [Accepted: 01/06/2023] [Indexed: 01/15/2023]
Abstract
Mesenchymal stem cells (MSCs) hold considerable promise for regenerative medicine. Optimization of the seeding density of mononuclear cells (MNCs) improves the proliferative and differentiation potential of isolated MSCs. However, the underlying mechanism is unclear. We cultured human bone marrow MNCs at various seeding densities (4.0 × 104, 1.25 × 105, 2.5 × 105, 6.0 × 105, 1.25 × 106 cells/cm2) and examined MSC colony formation. At lower seeding densities (4.0 × 104, 1.25 × 105 cells/cm2), colonies varied in diameter and density, from dense to sparse. In these colonies, the proportion of highly proliferative MSCs increased over time. In contrast, lower proliferative MSCs enlarged more rapidly. Senescent cells were removed using a short detachment treatment. We found that these mechanisms increase the purity of highly proliferative MSCs. Thereafter, we compared MSCs isolated under optimized conditions with a higher density (1.25 × 106 cells/cm2). MSCs under optimized conditions exhibited significantly higher proliferative and differentiation potential into adipocytes and chondrocytes, except for osteocytes. We propose the following conditions to improve MSC quality: (1) optimizing MNC seeding density to form single-cell colonies; (2) adjusting incubation times to increase highly proliferative MSCs; and (3) establishing a detachment processing time that excludes senescent cells.
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Affiliation(s)
- Hiroyuki Nagai
- Shibuya Corporation, Kanazawa 920-8681, Ishikawa, Japan
- Department of Clinical Laboratory Science, Faculty of Health Science, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Yamaguchi, Japan
| | - Akihiro Miwa
- Shibuya Corporation, Kanazawa 920-8681, Ishikawa, Japan
| | - Kenji Yoneda
- Shibuya Corporation, Kanazawa 920-8681, Ishikawa, Japan
| | - Koichi Fujisawa
- Department of Gastroenterology and Hepatology, Yamaguchi University School of Medicine, Ube 755-8505, Yamaguchi, Japan
- Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu 807-8555, Fukuoka, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University School of Medicine, Ube 755-8505, Yamaguchi, Japan
- Correspondence:
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13
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Martínez-Flores K, Plata-Rodríguez R, Olivos-Meza A, López-Macay A, Fernández-Torres J, Landa-Solís C, Zamudio-Cuevas Y. Osteogenic Potential of Monosodium Urate Crystals in Synovial Mesenchymal Stem Cells. Medicina (B Aires) 2022; 58:medicina58121724. [PMID: 36556927 PMCID: PMC9786019 DOI: 10.3390/medicina58121724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/08/2022] [Accepted: 11/18/2022] [Indexed: 11/26/2022] Open
Abstract
Background and Objectives: Deposits of monosodium urate (MSU) crystals due to increased levels of uric acid (UA) have been associated with bone formation and erosion, mainly in patients with chronic gout. The synovial membrane (SM) comprises several types of cells, including mesenchymal stem cells (SM-MSCs); however, it is unknown whether UA and MSU induce osteogenesis through SM-MSCs. Materials and Methods: Cultures of SM were immunotyped with CD44, CD69, CD90, CD166, CD105, CD34, and CD45 to identify MSCs. CD90+ cells were isolated by immunomagnetic separation (MACS), colony-forming units (CFU) were identified, and the cells were exposed to UA (3, 6.8, and 9 mg/dL) and MSU crystals (1, 5, and 10 μg/mL) for 3 weeks, and cellular morphological changes were evaluated. IL-1β and IL-6 were determined by ELISA, mineralization was assessed by alizarin red, and the expression of Runx2 was assessed by Western blot. Results: Cells derived from SM and after immunomagnetic separation were positive for CD90 (53 ± 8%) and CD105 (52 ± 18%) antigens, with 53 ± 5 CFU identified. Long-term exposure to SM-MSCs by UA and MSU crystals did not cause morphological damage or affect cell viability, nor were indicators of inflammation detected. Mineralization was observed at doses of 6.8 mg/dL UA and 5 μg/mL MSU crystals; however, the differences were not significant with respect to the control. The highest dose of MSU crystals (10 μg/mL) induced significant Runx2 expression with respect to the control (1.4 times greater) and SM-MSCs cultured in the osteogenic medium. Conclusions: MSU crystals may modulate osteogenic differentiation of SM-MSCs through an increase in Runx2.
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Affiliation(s)
- Karina Martínez-Flores
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Ricardo Plata-Rodríguez
- Facultad de Química, UNAM, Circuito Exterior S/N, Coyoacán, Cd. Universitaria, Mexico City 04510, Mexico
| | - Anell Olivos-Meza
- Servicio de Ortopedia del Deporte y Artroscopía, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Ambar López-Macay
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Javier Fernández-Torres
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
| | - Carlos Landa-Solís
- Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
- Correspondence: (C.L.-S.); (Y.Z.-C.); Tel.: +52-55-5999-1000 (ext. 19501) (Y.Z.-C.)
| | - Yessica Zamudio-Cuevas
- Laboratorio de Líquido Sinovial, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Mexico City 14389, Mexico
- Correspondence: (C.L.-S.); (Y.Z.-C.); Tel.: +52-55-5999-1000 (ext. 19501) (Y.Z.-C.)
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Bian Y, Wang H, Zhao X, Weng X. Meniscus repair: up-to-date advances in stem cell-based therapy. Stem Cell Res Ther 2022; 13:207. [PMID: 35578310 PMCID: PMC9109379 DOI: 10.1186/s13287-022-02863-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
The meniscus is a semilunar fibrocartilage between the tibia and femur that is essential for the structural and functional integrity of the keen joint. In addition to pain and knee joint dysfunction, meniscus injuries can also lead to degenerative changes of the knee joint such as osteoarthritis, which further affect patient productivity and quality of life. However, with intrinsic avascular property, the tearing meniscus tends to be nonunion and the augmentation of post-injury meniscus repair has long time been a challenge. Stem cell-based therapy with potent regenerative properties has recently attracted much attention in repairing meniscus injuries, among which mesenchymal stem cells were most explored for their easy availability, trilineage differentiation potential, and immunomodulatory properties. Here, we summarize the advances and achievements in stem cell-based therapy for meniscus repair in the last 5 years. We also highlight the obstacles before their successful clinical translation and propose some perspectives for stem cell-based therapy in meniscus repair.
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Affiliation(s)
- Yixin Bian
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Han Wang
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
| | - Xiuli Zhao
- Department of Medical Genetics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China.
| | - Xisheng Weng
- Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
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15
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Ding G, Du J, Hu X, Ao Y. Mesenchymal Stem Cells From Different Sources in Meniscus Repair and Regeneration. Front Bioeng Biotechnol 2022; 10:796367. [PMID: 35573249 PMCID: PMC9091333 DOI: 10.3389/fbioe.2022.796367] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 04/11/2022] [Indexed: 01/22/2023] Open
Abstract
Meniscus damage is a common trauma that often arises from sports injuries or menisci tissue degeneration. Current treatment methods focus on the repair, replacement, and regeneration of the meniscus to restore its original function. The advance of tissue engineering provides a novel approach to restore the unique structure of the meniscus. Recently, mesenchymal stem cells found in tissues including bone marrow, peripheral blood, fat, and articular cavity synovium have shown specific advantages in meniscus repair. Although various studies explore the use of stem cells in repairing meniscal injuries from different sources and demonstrate their potential for chondrogenic differentiation, their meniscal cartilage-forming properties are yet to be systematically compared. Therefore, this review aims to summarize and compare different sources of mesenchymal stem cells for meniscal repair and regeneration.
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Affiliation(s)
- Guocheng Ding
- Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Jianing Du
- School of Basic Medical Sciences, Peking University, Beijing, China
| | - Xiaoqing Hu
- Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
| | - Yingfang Ao
- Institute of Sports Medicine, Peking University Third Hospital, Beijing, China
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16
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Ozeki N, Koga H, Sekiya I. Degenerative Meniscus in Knee Osteoarthritis: From Pathology to Treatment. Life (Basel) 2022; 12:603. [PMID: 35455094 PMCID: PMC9032096 DOI: 10.3390/life12040603] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/31/2022] [Accepted: 04/14/2022] [Indexed: 12/16/2022] Open
Abstract
Knee osteoarthritis is a common degenerative joint disease characterized by chronic knee pain and disability in daily living. The lesion can involve the cartilage as well as the synovium, bone, ligaments, and meniscus, indicating a complicated pathology for knee osteoarthritis. The association with the meniscus has recently attracted much attention. Meniscal tears can initiate and progress knee osteoarthritis, with deleterious effects on the important roles of the meniscus in load distribution, shock absorption, and stability of the knee joint. Degenerative meniscus lesions are commonly observed in elderly people, but they have less impact on the prognosis of osteoarthritis. However, they are often accompanied by meniscal extrusion, which substantially decreases the hoop function of the meniscus and increases the risk of knee osteoarthritis. When surgical treatment is necessary, meniscal tears should be repaired to the greatest extent possible to preserve meniscus function. Long-term studies show better clinical outcomes and less degenerative osteoarthritis changes following meniscal repair than following partial meniscectomy. For meniscal extrusion repair, centralization techniques have been proposed that involve suturing the meniscus-capsule complex to the edge of the tibial plateau. Advancements in orthobiologics, such as platelet-rich plasma or stem cell therapy, have the potential to prevent the initiation or progression of osteoarthritis.
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Affiliation(s)
- Nobutake Ozeki
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan;
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan;
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan;
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17
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Mesenchymal Stromal Cells (MSCs) Isolated from Various Tissues of the Human Arthritic Knee Joint Possess Similar Multipotent Differentiation Potential. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12042239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
(1) Background: The mesenchymal stromal cells (MSCs) of different tissue origins are applied in cell-based chondrogenic regeneration. However, there is a lack of comparability determining the most suitable cell source for the tissue engineering (TE) of cartilage. The purpose of this study was to compare the in vitro chondrogenic potential of MSC-like cells from different tissue sources (bone marrow, meniscus, anterior cruciate ligament, synovial membrane, and the infrapatellar fat pad removed during total knee arthroplasty (TKA)) and define which cell source is best suited for cartilage regeneration. (2) Methods: MSC-like cells were isolated from five donors and expanded using adherent monolayer cultures. Differentiation was induced by culture media containing specific growth factors. Transforming growth factor (TGF)-ß1 was used as the growth factor for chondrogenic differentiation. Osteogenesis and adipogenesis were induced in monolayer cultures for 27 days, while pellet cell cultures were used for chondrogenesis for 21 days. Control cultures were maintained under the same conditions. After, the differentiation period samples were analyzed, using histological and immunohistochemical staining, as well as molecularbiological analysis by RT-PCR, to assess the expression of specific marker genes. (3) Results: Plastic-adherent growth and in vitro trilineage differentiation capacity of all isolated cells were proven. Flow cytometry revealed the clear co-expression of surface markers CD44, CD73, CD90, and CD105 on all isolated cells. Adipogenesis was validated through the formation of lipid droplets, while osteogenesis was proven by the formation of calcium deposits within differentiated cell cultures. The formation of proteoglycans was observed during chondrogenesis in pellet cultures, with immunohistochemical staining revealing an increased relative gene expression of collagen type II. RT-PCR proved an elevated expression of specific marker genes after successful differentiation, with no significant differences regarding different cell source of native tissue. (4) Conclusions: Irrespective of the cell source of native tissue, all MSC-like cells showed multipotent differentiation potential in vitro. The multipotent differentiation capacity did not differ significantly, and chondrogenic differentiation was proven in all pellet cultures. Therefore, cell suitability for cell-based cartilage therapies and tissue engineering is given for various tissue origins that are routinely removed during total knee arthroplasty (TKA). This study might provide essential information for the clinical tool of cell harvesting, leading to more flexibility in cell availability.
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18
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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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19
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Linde PE, Puttlitz CM, Kisiday JD. Adult ovine connective tissue cells resemble mesenchymal stromal cells in their propensity for extensive ex vivo expansion. Connect Tissue Res 2021; 62:671-680. [PMID: 33153311 DOI: 10.1080/03008207.2020.1847099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Purpose/Aim: Expanded, human connective tissue cells can adopt mesenchymal stromal cell (MSC) properties that are favorable for applications in regenerative medicine. Sheep are used as a large animal model for cell therapies, although for preclinical testing it is important to establish whether ovine cells resemble humans in their tendency to adopt MSC properties. The objective of this study was to investigate whether cells from five ovine connective tissues are MSC-like in their propensity for extensive expansion and immunophenotype.Materials and Methods: Monolayer cultures were established with cells from annulus fibrosus, cartilage, meniscus, tendon, and nucleus pulposus. Bone marrow MSCs were evaluated as a control. Cultures were seeded at 500 cells/cm2, and subcultured every 5 days up to day 20. Flow cytometry was used to evaluate expression of cluster of differentiation (CD) molecules associated with MSCs (29, 44, 166). Colony formation was evaluated using time-lapse imaging of individual cells.Results: By day 20, cumulative population doublings ranged between 22 (chondrocytes) and 27 (MSCs). All cells uniformly expressed CD44 and 73. Expression of CD166 for MSCs was 98-99%, and ranged between 64 and 97% for the other cell types. Time-lapse imaging demonstrated that 58-94% of the cells colonized as indicated by 3 population doublings within 52 hours.Conclusions: Cells from ovine connective tissues resembled MSCs in their propensity for sustained, colony-forming growth and expression of CD molecules. These data supports the potential for preclinical testing of MSC-like connective tissue cells in sheep.
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Affiliation(s)
- Peter E Linde
- Orthopaedic Bioengineering Research Laboratory, Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado, USA
| | - Christian M Puttlitz
- Orthopaedic Bioengineering Research Laboratory, Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado, USA
| | - John D Kisiday
- Orthopaedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado, USA
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20
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Korpershoek JV, Rikkers M, de Windt TS, Tryfonidou MA, Saris DBF, Vonk LA. Selection of Highly Proliferative and Multipotent Meniscus Progenitors through Differential Adhesion to Fibronectin: A Novel Approach in Meniscus Tissue Engineering. Int J Mol Sci 2021; 22:ijms22168614. [PMID: 34445320 PMCID: PMC8395239 DOI: 10.3390/ijms22168614] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/05/2021] [Accepted: 08/07/2021] [Indexed: 12/26/2022] Open
Abstract
Meniscus injuries can be highly debilitating and lead to knee osteoarthritis. Progenitor cells from the meniscus could be a superior cell type for meniscus repair and tissue-engineering. The purpose of this study is to characterize meniscus progenitor cells isolated by differential adhesion to fibronectin (FN-prog). Human osteoarthritic menisci were digested, and FN-prog were selected by differential adhesion to fibronectin. Multilineage differentiation, population doubling time, colony formation, and MSC surface markers were assessed in the FN-prog and the total meniscus population (Men). Colony formation was compared between outer and inner zone meniscus digest. Chondrogenic pellet cultures were performed for redifferentiation. FN-prog demonstrated multipotency. The outer zone FN-prog formed more colonies than the inner zone FN-prog. FN-prog displayed more colony formation and a higher proliferation rate than Men. FN-prog redifferentiated in pellet culture and mostly adhered to the MSC surface marker profile, except for HLA-DR receptor expression. This is the first study that demonstrates differential adhesion to fibronectin for the isolation of a progenitor-like population from the meniscus. The high proliferation rates and ability to form meniscus extracellular matrix upon redifferentiation, together with the broad availability of osteoarthritis meniscus tissue, make FN-prog a promising cell type for clinical translation in meniscus tissue-engineering.
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Affiliation(s)
- Jasmijn V. Korpershoek
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (J.V.K.); (M.R.); (T.S.d.W.); (D.B.F.S.)
| | - Margot Rikkers
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (J.V.K.); (M.R.); (T.S.d.W.); (D.B.F.S.)
| | - Tommy S. de Windt
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (J.V.K.); (M.R.); (T.S.d.W.); (D.B.F.S.)
| | - Marianna A. Tryfonidou
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands;
| | - Daniel B. F. Saris
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (J.V.K.); (M.R.); (T.S.d.W.); (D.B.F.S.)
- Department of Orthopedic Surgery and Sports Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Department of Reconstructive medicine, University of Twente, 7522 NB Enschede, The Netherlands
| | - Lucienne A. Vonk
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (J.V.K.); (M.R.); (T.S.d.W.); (D.B.F.S.)
- Correspondence: ; Tel.: +49-0-3328-4346-25
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21
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Sekiya I, Katano H, Mizuno M, Koga H, Masumoto J, Tomita M, Ozeki N. Alterations in cartilage quantification before and after injections of mesenchymal stem cells into osteoarthritic knees. Sci Rep 2021; 11:13832. [PMID: 34226650 PMCID: PMC8257723 DOI: 10.1038/s41598-021-93462-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/04/2021] [Indexed: 01/22/2023] Open
Abstract
Several studies have reported improvement in knee pain following mesenchymal stem cell (MSC) injections for knee osteoarthritis (OA). We developed a novel 3D magnetic resonance imaging (MRI) analysis software program that provides “projected cartilage area ratios” for automatic detection of changes in cartilage amounts. The primary objective of this prospective interventional study was to compare alterations in the projected cartilage area ratio (thickness ≥ 1.5 mm) at the femoral posteromedial region between 30 weeks before and 30 weeks after synovial MSC injections. Secondary objectives were to assess the clinical scores and safety of MSC injections. Patients with OA who complained of knee pain underwent autologous synovial MSC injections into the knee at time 0 and again 15 weeks later. MRI examinations were performed at − 30, − 15, − 1, and 30 weeks. Patients showing < 3% decreases in the projected cartilage area ratio (thickness ≥ 1.5 mm) at the femoral the posteromedial region from − 30 weeks to − 15 weeks were excluded from the study. The Lysholm Knee Score, Knee Injury and Osteoarthritis Outcome Scale (KOOS), and Numerical Rating Scale (NRS) scores were evaluated at − 30, − 15, − 5, − 2, 0, 5, 10, 15, 20, 25, and 30 weeks. Five patients were excluded because 3D MRI analysis showed no cartilage loss at − 15 weeks. Ultimately, eight OA patients underwent MSC injections. The projected cartilage area ratio significantly decreased by 0.07 in the 30 weeks before MSC injections (p = 0.01), but no further decreases occurred in the 30 weeks after MSC injections. The projected cartilage area ratio at the femoral posteromedial region showed a significant difference between 30 weeks before and 30 weeks after MSC injections. The Lysholm Knee Score, KOOS, and NRS values improved significantly after the injections. MSC injection could not be ruled out as the cause of two adverse events: transient knee pain and itching in both hands. Fully automatic 3D MRI analysis showed that synovial MSC injections suppressed cartilage loss in patients with progressive OA. Trial registration: Intraarticular injections of synovial stem cells for osteoarthritis of the knee (Number UMIN 000026732). Date of registration; June 1, 2017. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000029967.
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Affiliation(s)
- Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
| | - Hisako Katano
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Mitsuru Mizuno
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | | | - Makoto Tomita
- School of Data Science, Graduate School of Data Science, Yokohama City University, Yokohama, Japan
| | - Nobutake Ozeki
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
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22
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Autologous Minimally Invasive Cell-Based Therapy for Meniscal and Anterior Cruciate Ligament Regeneration. Case Rep Orthop 2021; 2021:6614232. [PMID: 34258092 PMCID: PMC8253646 DOI: 10.1155/2021/6614232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 06/02/2021] [Accepted: 06/06/2021] [Indexed: 01/16/2023] Open
Abstract
The meniscus is a fibrocartilaginous tissue that acts as a “shock absorber,” along with performing functions such as stabilization and lubrication of the joint, proprioception, and load distribution. Sudden twisting movements during weight bearing or trauma can cause injury to the menisci, which leads to symptoms such as pain, swelling, and difficulty in performing movements, among others. Conventional pharmacological and surgical treatments are effective in treating the condition; however, do not result in regeneration of healthy tissues. In this report, we highlight the role of cell-based therapy in the management of medial and lateral meniscal and anterior cruciate ligament tears in a patient who was unwilling to undergo surgical treatment. We injected autologous mesenchymal stem cells obtained from the bone marrow and adipose tissue and platelet-rich plasma into the joint of the patient at the area of injury, as well as intravenously. The results of our study corroborate with those previously reported in the literature regarding the improvement in clinical parameters and regeneration of meniscal tissue and ligament. Thus, based on previous literature and improvements noticed in our patient, cell-based therapy can be considered a safe and effective therapeutic modality in the treatment of meniscal tears and cruciate ligament injury.
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23
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Ozeki N, Nakagawa Y, Mizuno M, Kohno Y, Katano H, Koga H, Sekiya I. Ultrasound-Guided Harvesting of Synovium for Regenerative Medicine of Cartilage and Meniscus Using Synovial Mesenchymal Stem Cells. Arthrosc Tech 2021; 10:e1723-e1727. [PMID: 34336570 PMCID: PMC8322568 DOI: 10.1016/j.eats.2021.03.020] [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: 01/05/2021] [Accepted: 03/09/2021] [Indexed: 02/03/2023] Open
Abstract
Mesenchymal stem cell (MSC) therapy for cartilage or meniscus pathologies, including osteoarthritis, requires the easy and safe collection of MSC source materials. Synovial MSCs are attractive cell sources for joint pathology because of their high proliferative and chondrogenic potential in vitro and in vivo. We developed an ultrasound-guided harvesting procedure for synovium for the regenerative medicine of cartilage and meniscus. A ∼1-cm skin incision is made at the proximal side of the patellae, and a forceps is inserted under ultrasound guidance of the suprapatellar pouch to grasp the synovium. Here, several synovium samples were retrieved and transported sterilely for culture at the cell-processing facility. After a 14-day culture of the nucleated cells, crystal violet confirmed colony formation. Cell growth was enough for MSC therapy of joint pathology (0.89 ± 0.06 × 106 cells/dish). No adverse events occurred during synovium harvesting. A key advantage of this procedure is its minimal invasiveness, as synovium is harvested from a 1-cm skin incision in the knee joint. A disadvantage is the possible risk of hemostasis, as arresting bleeding at the synovial harvest site is difficult, even though the suprapatellar pouch contains no major vessels.
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Affiliation(s)
- Nobutake Ozeki
- Center for Stem Cell and Regenerative Medicine, Tokyo, Japan,Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Yusuke Nakagawa
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Mitsuru Mizuno
- Center for Stem Cell and Regenerative Medicine, Tokyo, Japan
| | - Yuji Kohno
- Center for Stem Cell and Regenerative Medicine, Tokyo, Japan,Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Hisako Katano
- Center for Stem Cell and Regenerative Medicine, Tokyo, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan,Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo, Japan,Department of Orthopaedic Surgery, Tokyo Medical and Dental University Hospital of Medicine, Tokyo, Japan,Address correspondence to Ichiro Sekiya, M.D., Ph.D., Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510 Japan.
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24
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Wei Y, Sun H, Gui T, Yao L, Zhong L, Yu W, Heo SJ, Han L, Dyment NA, Liu XS, Zhang Y, Koyama E, Long F, Zgonis MH, Mauck RL, Ahn J, Qin L. The critical role of Hedgehog-responsive mesenchymal progenitors in meniscus development and injury repair. eLife 2021; 10:e62917. [PMID: 34085927 PMCID: PMC8177886 DOI: 10.7554/elife.62917] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 05/18/2021] [Indexed: 12/18/2022] Open
Abstract
Meniscal tears are associated with a high risk of osteoarthritis but currently have no disease-modifying therapies. Using a Gli1 reporter line, we found that Gli1+ cells contribute to the development of meniscus horns from 2 weeks of age. In adult mice, Gli1+ cells resided at the superficial layer of meniscus and expressed known mesenchymal progenitor markers. In culture, meniscal Gli1+ cells possessed high progenitor activities under the control of Hh signal. Meniscus injury at the anterior horn induced a quick expansion of Gli1-lineage cells. Normally, meniscal tissue healed slowly, leading to cartilage degeneration. Ablation of Gli1+ cells further hindered this repair process. Strikingly, intra-articular injection of Gli1+ meniscal cells or an Hh agonist right after injury accelerated the bridging of the interrupted ends and attenuated signs of osteoarthritis. Taken together, our work identified a novel progenitor population in meniscus and proposes a new treatment for repairing injured meniscus and preventing osteoarthritis.
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MESH Headings
- Animals
- Cell Lineage
- Cell Proliferation
- Disease Models, Animal
- Hedgehog Proteins/genetics
- Hedgehog Proteins/metabolism
- Humans
- Male
- Menisci, Tibial/metabolism
- Menisci, Tibial/pathology
- Menisci, Tibial/surgery
- Mesenchymal Stem Cell Transplantation
- Mesenchymal Stem Cells/metabolism
- Mice, Knockout
- Osteoarthritis, Knee/genetics
- Osteoarthritis, Knee/metabolism
- Osteoarthritis, Knee/pathology
- Osteoarthritis, Knee/prevention & control
- Signal Transduction
- Swine
- Swine, Miniature
- Tibial Meniscus Injuries/genetics
- Tibial Meniscus Injuries/metabolism
- Tibial Meniscus Injuries/pathology
- Tibial Meniscus Injuries/surgery
- Time Factors
- Wound Healing
- Zinc Finger Protein GLI1/genetics
- Zinc Finger Protein GLI1/metabolism
- Mice
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Affiliation(s)
- Yulong Wei
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Hao Sun
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen UniversityGuangzhouChina
| | - Tao Gui
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan UniversityGuangzhouChina
| | - Lutian Yao
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Leilei Zhong
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Wei Yu
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanChina
| | - Su-Jin Heo
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical CenterPhiladelphiaUnited States
| | - Lin Han
- School of Biomedical Engineering, Science and Health Systems, Drexel UniversityPhiladelphiaUnited States
| | - Nathaniel A Dyment
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Xiaowei Sherry Liu
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Yejia Zhang
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical CenterPhiladelphiaUnited States
- Department of Physical Medicine and Rehabilitation, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Eiki Koyama
- Translational Research Program in Pediatric Orthopaedics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Fanxin Long
- Translational Research Program in Pediatric Orthopaedics, The Children's Hospital of PhiladelphiaPhiladelphiaUnited States
| | - Miltiadis H Zgonis
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
| | - Robert L Mauck
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical CenterPhiladelphiaUnited States
| | - Jaimo Ahn
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
- Department of Orthopaedic Surgery, University of Michigan Medical SchoolAnn ArborUnited States
| | - Ling Qin
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of PennsylvaniaPhiladelphiaUnited States
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25
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Hagmeijer MH, Korpershoek JV, Crispim JF, Chen LT, Jonkheijm P, Krych AJ, Saris DBF, Vonk LA. The regenerative effect of different growth factors and platelet lysate on meniscus cells and mesenchymal stromal cells and proof of concept with a functionalized meniscus implant. J Tissue Eng Regen Med 2021; 15:648-659. [PMID: 33982442 PMCID: PMC8362003 DOI: 10.1002/term.3218] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 01/04/2021] [Accepted: 05/06/2021] [Indexed: 12/11/2022]
Abstract
Meniscus regeneration could be enhanced by targeting meniscus cells and mesenchymal stromal cells (MSCs) with the right growth factors. Combining these growth factors with the Collagen Meniscus Implant (CMI®) could accelerate cell ingrowth and tissue formation in the implant and thereby improve clinical outcomes. Using a transwell migration assay and a micro-wound assay, the effect of insulin-like growth factor-1, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), transforming growth factor beta 1 (TGF-β1), fibroblast growth factor, and platelet lysate (PL) on migration and proliferation of meniscus cells and MSCs was assessed. The formation of extracellular matrix under influence of the above-mentioned growth factors was assessed after 28 days of culture of both MSCs and meniscus cells. As a proof of concept, the CMI® was functionalized with a VEGF binding peptide and coated with platelet-rich plasma (PRP) for clinical application. Our results demonstrate that PDGF, TGF-β1, and PL stimulate migration, proliferation, and/or extracellular matrix production of meniscus cells and MSCs. Additionally, the CMI® was successfully functionalized with a VEGF binding peptide and PRP which increased migration of meniscus cell and MSC into the implant. This study demonstrates proof of concept of functionalizing the CMI® with growth factor binding peptides. A CMI® functionalized with the right growth factors holds great potential for meniscus replacement after partial meniscectomy.
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Affiliation(s)
- Michella H Hagmeijer
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jasmijn V Korpershoek
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - João F Crispim
- Developmental Bioengineering, University of Twente, Enschede, The Netherlands.,Department of Molecules and Materials, MESA+ Institute for Nanotechnology, University of Twente, Enschede, The Netherlands
| | - Li-Ting Chen
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Pascal Jonkheijm
- Department of Molecules and Materials, MESA+ Institute for Nanotechnology, University of Twente, Enschede, The Netherlands
| | - Aaron J Krych
- Department of Orthopedic Surgery and Sports Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Daniel B F Saris
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, The Netherlands.,Developmental Bioengineering, University of Twente, Enschede, The Netherlands.,Department of Orthopedic Surgery and Sports Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Lucienne A Vonk
- Department of Orthopedics, University Medical Center Utrecht, Utrecht, The Netherlands
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26
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Research Progress on Stem Cell Therapies for Articular Cartilage Regeneration. Stem Cells Int 2021; 2021:8882505. [PMID: 33628274 PMCID: PMC7895563 DOI: 10.1155/2021/8882505] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/11/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023] Open
Abstract
Injury of articular cartilage can cause osteoarthritis and seriously affect the physical and mental health of patients. Unfortunately, current surgical treatment techniques that are commonly used in the clinic cannot regenerate articular cartilage. Regenerative medicine involving stem cells has entered a new stage and is considered the most promising way to regenerate articular cartilage. In terms of theories on the mechanism, it was thought that stem cell-mediated articular cartilage regeneration was achieved through the directional differentiation of stem cells into chondrocytes. However, recent evidence has shown that the stem cell secretome plays an important role in biological processes such as the immune response, inflammation regulation, and drug delivery. At the same time, the stem cell secretome can effectively mediate the process of tissue regeneration. This new theory has attributed the therapeutic effect of stem cells to their paracrine effects. The application of stem cells is not limited to exogenous stem cell transplantation. Endogenous stem cell homing and in situ regeneration strategies have received extensive attention. The application of stem cell derivatives, such as conditioned media, extracellular vesicles, and extracellular matrix, is an extension of stem cell paracrine theory. On the other hand, stem cell pretreatment strategies have also shown promising therapeutic effects. This article will systematically review the latest developments in these areas, summarize challenges in articular cartilage regeneration strategies involving stem cells, and describe prospects for future development.
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27
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Ozeki N, Kohno Y, Kushida Y, Watanabe N, Mizuno M, Katano H, Masumoto J, Koga H, Sekiya I. Synovial mesenchymal stem cells promote the meniscus repair in a novel pig meniscus injury model. J Orthop Res 2021; 39:177-183. [PMID: 32886427 PMCID: PMC7821148 DOI: 10.1002/jor.24846] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 08/20/2020] [Accepted: 09/02/2020] [Indexed: 02/04/2023]
Abstract
Stem cell therapy has potential for the treatment of degenerative meniscus injuries; however, an optimal animal model has not been established. Basic and clinical research show that synovial mesenchymal stem cells (MSCs) promote meniscus repair. The purposes of this study were to create a novel meniscus injury model in microminipigs and to investigate the effectiveness of synovial MSCs on meniscus healing in this model. The posterior portion of the medial meniscus in microminipigs was punctuated 200 times with a 23G needle. Allogenic synovial MSC suspension was placed on the injury site for 10 min for transplantation. The meniscus was evaluated histologically and via sagittal magnetic resonance imaging (MRI), radial MRI reconstructed in three dimensional, and T2 mapping at 1 and 8 weeks. Proteoglycan content stained with safranin-o disappeared 1 week after treatment in both the MSC and control groups but increased at 8 weeks only in the MSC group. Histological scores at 8 weeks were significantly higher in the MSC group than in the control group (n = 6). At 8 weeks, the T2 values of the MSC group were significantly closer to those of a normal meniscus than were those of the control group. High signal intensity areas of the MRIs and positive areas stained with picrosirius red coincided with meniscal lesions. In conclusion, we created a novel meniscus injury model in microminipigs. Evaluation via histology, MRIs, and polarized microscopy showed that transplantation of synovial MSCs improved meniscus healing.
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Affiliation(s)
- Nobutake Ozeki
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental UniversityTokyoJapan
| | - Yuji Kohno
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental UniversityTokyoJapan
| | - Yoshihisa Kushida
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental UniversityTokyoJapan
| | - Naoto Watanabe
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental UniversityTokyoJapan
| | - Mitsuru Mizuno
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental UniversityTokyoJapan
| | - Hisako Katano
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental UniversityTokyoJapan
| | | | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Graduate School of Medical and Dental SciencesTokyo Medical and Dental UniversityTokyoJapan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative MedicineTokyo Medical and Dental UniversityTokyoJapan
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28
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Chahla J, Papalamprou A, Chan V, Arabi Y, Salehi K, Nelson TJ, Limpisvasti O, Mandelbaum BR, Tawackoli W, Metzger MF, Sheyn D. Assessing the Resident Progenitor Cell Population and the Vascularity of the Adult Human Meniscus. Arthroscopy 2021; 37:252-265. [PMID: 32979500 PMCID: PMC7829352 DOI: 10.1016/j.arthro.2020.09.021] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 09/09/2020] [Accepted: 09/10/2020] [Indexed: 02/02/2023]
Abstract
PURPOSE To identify, characterize, and compare the resident progenitor cell populations within the red-red, red-white, and white-white (WW) zones of freshly harvested human cadaver menisci and to characterize the vascularity of human menisci using immunofluorescence and 3-dimensional (3D) imaging. METHODS Fresh adult human menisci were harvested from healthy donors. Menisci were enzymatically digested, mononuclear cells isolated, and characterized using flow cytometry with antibodies against mesenchymal stem cell surface markers (CD105, CD90, CD44, and CD29). Cells were expanded in culture, characterized, and compared with bone marrow-derived mesenchymal stem cells. Trilineage differentiation potential of cultured cells was determined. Vasculature of menisci was mapped in 3D using a modified uDisco clearing and immunofluorescence against vascular markers CD31, lectin, and alpha smooth muscle actin. RESULTS There were no significant differences in the clonogenicity of isolated cells between the 3 zones. Flow cytometry showed presence of CD44+CD105+CD29+CD90+ cells in all 3 zones with high prevalence in the WW zone. Progenitors from all zones were found to be potent to differentiate to mesenchymal lineages. Larger vessels in the red-red zone of meniscus were observed spanning toward red-white, sprouting to smaller arterioles and venules. CD31+ cells were identified in all zones using the 3D imaging and co-localization of additional markers of vasculature (lectin and alpha smooth muscle actin) was observed. CONCLUSIONS The presence of resident mesenchymal progenitors was evident in all 3 meniscal zones of healthy adult donors without injury. In addition, our results demonstrate the presence of vascularization in the WW zone. CLINICAL RELEVANCE The existence of progenitors and presence of microvasculature in the WW zone of the meniscus suggests the potential for repair and biologic augmentation strategies in that zone of the meniscus in young healthy adults. Further research is necessary to fully define the functionality of the meniscal blood supply and its implications for repair.
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Affiliation(s)
- Jorge Chahla
- Kerlan Jobe Institute, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A
| | - Angela Papalamprou
- Orthopedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A
| | - Virginia Chan
- Orthopedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A
| | - Yasaman Arabi
- Orthopedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A
| | - Khosrawdad Salehi
- Orthopedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A
| | - Trevor J Nelson
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A
| | - Orr Limpisvasti
- Kerlan Jobe Institute, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A
| | - Bert R Mandelbaum
- Kerlan Jobe Institute, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A
| | - Wafa Tawackoli
- Orthopedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A
| | - Melodie F Metzger
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A
| | - Dmitriy Sheyn
- Kerlan Jobe Institute, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Orthopedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A.; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, U.S.A..
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An YH, Kim JA, Yim HG, Han WJ, Park YB, Jin Park H, Young Kim M, Jang J, Koh RH, Kim SH, Hwang NS, Ha CW. Meniscus regeneration with injectable Pluronic/PMMA-reinforced fibrin hydrogels in a rabbit segmental meniscectomy model. J Tissue Eng 2021; 12:20417314211050141. [PMID: 34721832 PMCID: PMC8552387 DOI: 10.1177/20417314211050141] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 09/15/2021] [Indexed: 01/19/2023] Open
Abstract
Injectable hydrogel systems are a facile approach to apply to the damaged meniscus in a minimally invasive way. We herein developed a clinically applicable and injectable semi-interpenetrated network (semi-IPN) hydrogel system based on fibrin (Fb), reinforced with Pluronic F127 (F127) and polymethyl methacrylate (PMMA), to improve the intrinsic weak mechanical properties. Through the dual-syringe device system, the hydrogel could form a gel state within about 50 s, and the increment of compressive modulus of Fb hydrogels was achieved by adding F127 from 3.0% (72.0 ± 4.3 kPa) to 10.0% (156.0 ± 9.8 kPa). The shear modulus was enhanced by adding PMMA microbeads (26.0 ± 1.1 kPa), which was higher than Fb (13.5 ± 0.5 kPa) and Fb/F127 (21.7 ± 0.8 kPa). Moreover, the addition of F127 and PMMA also delayed the rate of enzymatic biodegradation of Fb hydrogel. Finally, we confirmed that both Fb/F127 and Fb/F127/PMMA hydrogels showed accelerated tissue repair in the in vivo segmental defect of the rabbit meniscus model. In addition, the histological analysis showed that the quality of the regenerated tissues healed by Fb/F127 was particularly comparable to that of healthy tissue. The biomechanical strength of the regenerated tissues of Fb/F127 (3.50 ± 0.35 MPa) and Fb/F127/PMMA (3.59 ± 0.89 MPa) was much higher than that of Fb (0.82 ± 0.05 MPa) but inferior to that of healthy tissue (6.63 ± 1.12 MPa). These results suggest that the reinforcement of Fb hydrogel using FDA-approved synthetic biomaterials has great potential to be used clinically.
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Affiliation(s)
- Young-Hyeon An
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea
- Bio-MAX/N-Bio Institute, Institute of Bioengineering, Seoul National University, Seoul, Republic of Korea
| | - Jin-A Kim
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
- Stem Cell & Regenerative Medicine Research Institute, Samsung Medical Center, Seoul, Republic of Korea
| | - Hyun-Gu Yim
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea
| | - Woo-Jung Han
- Stem Cell & Regenerative Medicine Research Institute, Samsung Medical Center, Seoul, Republic of Korea
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yong-Beom Park
- Department of Orthopedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - Hyun Jin Park
- Stem Cell & Regenerative Medicine Research Institute, Samsung Medical Center, Seoul, Republic of Korea
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Man Young Kim
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jaewon Jang
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Racheal H. Koh
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea
| | - Su-Hwan Kim
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, Republic of Korea
- Department of Chemical Engineering (BK21 FOUR), Dong-A University, Busan, Republic of Korea
| | - Nathaniel S. Hwang
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea
- Bio-MAX/N-Bio Institute, Institute of Bioengineering, Seoul National University, Seoul, Republic of Korea
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul, Republic of Korea
| | - Chul-Won Ha
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
- Stem Cell & Regenerative Medicine Research Institute, Samsung Medical Center, Seoul, Republic of Korea
- Department of Orthopedic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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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: 12] [Impact Index Per Article: 2.4] [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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LOXL2 promotes aggrecan and gender-specific anabolic differences to TMJ cartilage. Sci Rep 2020; 10:20179. [PMID: 33214607 PMCID: PMC7678826 DOI: 10.1038/s41598-020-77178-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 11/05/2020] [Indexed: 12/24/2022] Open
Abstract
In the United States, 5–12% of adults have at least one symptom of temporomandibular joint (TMJ) disorders, including TMJ osteoarthritis (TMJ-OA). However, there is no chondroprotective agent that is approved for clinical application. We showed that LOXL2 is elevated in the regenerative response during fracture healing in mice and has a critical role in chondrogenic differentiation. Indeed, LOXL2 is an anabolic effector that attenuates pro-inflammatory signaling in OA cartilage of the TMJ and knee joint, induces chondroprotective and regenerative responses, and attenuates NF-kB signaling. The specific goal of the study was to evaluate if adenoviral delivery of LOXL2 is anabolic to human and mouse TMJ condylar cartilage in vivo and evaluate the protective and anabolic effect on cartilage-specific factors. We employed two different models to assess TMJ-OA. In one model, clinical TMJ-OA cartilage from 5 different samples in TMJ-OA cartilage plugs were implanted subcutaneously in nude mice. Adenovirus LOXL2 -treated implants showed higher mRNA levels of LOXL2, ACAN, and other anabolic genes compared to the adenovirus-Empty-treated implants. Further characterization by RNA-seq analysis showed LOXL2 promotes proteoglycan networks and extracellular matrix in human TMJ-OA cartilage implants in vivo. In order to evaluate if LOXL2-induced functional and sex-linked differences, both male and female four-month-old chondrodysplasia (Cho/+) mice, which develop progressive TMJ-OA due to a point mutation in the Col11a1 gene, were subjected to intraperitoneal injection with Adv-RFP-LOXL2 every 2 weeks for 12 weeks. The data showed that adenovirus delivery of LOXL2 upregulated LOXL2 and aggrecan (Acan), whereas MMP13 expression was slightly downregulated. The fold change expression of Acan and Runx2 induced by Adv-RFP-LOXL2 was higher in females compared to males. Interestingly, Adv-RFP-LOXL2 injection significantly increased Rankl expression in male but there was no change in females, whereas VegfB gene expression was increased in females, but not in males, as compared to those injected with Adv-RFP-Empty in respective groups. Our findings indicate that LOXL2 can induce specifically the expression of Acan and other anabolic genes in two preclinical models in vivo. Further, LOXL2 has beneficial functions in human TMJ-OA cartilage implants and promotes gender-specific anabolic responses in Cho/+ mice with progressive TMJ-OA, suggesting its merit for further study as an anabolic therapy for TMJ-OA.
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Shah S, Otsuka T, Bhattacharjee M, Laurencin CT. Minimally Invasive Cellular Therapies for Osteoarthritis Treatment. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2020. [DOI: 10.1007/s40883-020-00184-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Yang Z, Li H, Yuan Z, Fu L, Jiang S, Gao C, Wang F, Zha K, Tian G, Sun Z, Huang B, Wei F, Cao F, Sui X, Peng J, Lu S, Guo W, Liu S, Guo Q. Endogenous cell recruitment strategy for articular cartilage regeneration. Acta Biomater 2020; 114:31-52. [PMID: 32652223 DOI: 10.1016/j.actbio.2020.07.008] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 07/02/2020] [Accepted: 07/02/2020] [Indexed: 02/07/2023]
Abstract
In the absence of timely and proper treatments, injuries to articular cartilage (AC) can lead to cartilage degeneration and ultimately result in osteoarthritis. Regenerative medicine and tissue engineering techniques are emerging as promising approaches for AC regeneration and repair. Although the use of cell-seeded scaffolds prior to implantation can regenerate and repair cartilage lesions to some extent, these approaches are still restricted by limited cell sources, excessive costs, risks of disease transmission and complex manufacturing practices. Recently developed acellular scaffold approaches that rely on the recruitment of endogenous cells to the injured sites avoid these drawbacks and offer great promise for in situ AC regeneration. Multiple endogenous stem/progenitor cells (ESPCs) are found in joint-resident niches and have the capability to migrate to sites of injury to participate in AC regeneration. However, the natural recruitment of ESPCs is insufficient, and the local microenvironment is hostile after injury. Hence, an endogenous cell recruitment strategy based on the combination of chemoattractants and acellular scaffolds to effectively and specifically recruit ESPCs and improve local microenvironment may provide new insights into in situ AC regeneration. This review provides a brief overview of: (1) the status of endogenous cell recruitment strategy; (2) the subpopulations, potential migration routes (PMRs) of joint-resident ESPCs and their immunomodulatory and reparative effects; (3) chemoattractants and their potential adverse effects; (4) scaffold-based drug delivery systems (SDDSs) that are utilized for in situ AC regeneration; and (5) the challenges and future perspectives of endogenous cell recruitment strategy for AC regeneration. STATEMENT OF SIGNIFICANCE: Although the endogenous cell recruitment strategy for articular cartilage (AC) regeneration has been investigated for several decades, much work remains to be performed in this field. Future studies should have the following aims: (1) reporting the up-to-date progress in the endogenous cell recruitment strategies; (2) determining the subpopulations of ESPCs, the cellular and molecular mechanisms underlying the migration of these cells and their anti-inflammatory, immunomodulatory and reparative effects; (3) elucidating the chemoattractants that enhance ESPC recruitment and their potential adverse effects; and (4) developing advanced SDDSs for chemoattractant dispatch. Herein, we present a systematic overview of the aforementioned issues to provide a better understanding of endogenous cell recruitment strategies for AC regeneration and repair.
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Kisiday JD, Liebig BE, Goodrich LR. Adult ovine chondrocytes in expansion culture adopt progenitor cell properties that are favorable for cartilage tissue engineering. J Orthop Res 2020; 38:1996-2005. [PMID: 32222117 PMCID: PMC8442064 DOI: 10.1002/jor.24671] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 02/18/2020] [Accepted: 03/06/2020] [Indexed: 02/04/2023]
Abstract
Human chondrocytes in expansion culture can become progenitor-like in their ability to proliferate extensively and secrete neocartilage in chondrogenic culture. Sheep are used as a large animal model for cartilage tissue engineering, although for testing progenitor-like chondrocytes it is important that ovine chondrocytes resemble human in the ability to adopt progenitor properties. Here, we investigate whether ovine chondrocytes can adopt progenitor properties as indicated by rapid proliferation in a colony-forming fashion, and high levels of neocartilage secretion in chondrogenic culture. In conditions known to promote expansion of mesenchymal stromal cells, ovine chondrocytes proliferated through approximately 12 population doublings in 10 days. Time-lapse imaging indicated rapid proliferation in a colony-forming pattern. Expanded ovine chondrocytes that were seeded into agarose and cultured in chondrogenic medium accumulated neocartilage over 2 weeks, to a greater extent than primary chondrocytes. These data confirm that ovine chondrocytes resemble human chondrocytes in their ability to acquire progenitor properties that are important for cartilage tissue engineering. Given the broad interest in using progenitor cells to heal connective tissues, next we compared proliferation and trilineage differentiation of ovine chondrocytes, meniscus cells, and tenocytes. Meniscus cells and tenocytes experienced more than 13 population doublings in 10 days. In chondrogenic culture, cartilage matrix accumulation, and gene expression were largely similar among the cell types. All cell types resisted osteogenesis, while expanded tenocytes and meniscal cells were capable of adipogenesis. While ovine connective tissue cells demonstrated limited lineage plasticity, these data support the potential to promote certain progenitor properties with expansion.
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Affiliation(s)
- John D. Kisiday
- Department of Clinical Sciences, Orthopaedic Reserch CenterC. Wayne McIlwraith Translational Medicine Institute Fort Collins Colorado
| | - Bethany E. Liebig
- Department of Clinical Sciences, Orthopaedic Reserch CenterC. Wayne McIlwraith Translational Medicine Institute Fort Collins Colorado
| | - Laurie R. Goodrich
- Department of Clinical Sciences, Orthopaedic Reserch CenterC. Wayne McIlwraith Translational Medicine Institute Fort Collins Colorado
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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: 22] [Impact Index Per Article: 4.4] [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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Wagenbrenner M, Heinz T, Horas K, Jakuscheit A, Arnholdt J, Herrmann M, Rudert M, Holzapfel BM, Steinert AF, Weißenberger M. The human arthritic hip joint is a source of mesenchymal stromal cells (MSCs) with extensive multipotent differentiation potential. BMC Musculoskelet Disord 2020; 21:297. [PMID: 32404085 PMCID: PMC7222515 DOI: 10.1186/s12891-020-03340-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 05/08/2020] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND While multiple in vitro studies examined mesenchymal stromal cells (MSCs) derived from bone marrow or hyaline cartilage, there is little to no data about the presence of MSCs in the joint capsule or the ligamentum capitis femoris (LCF) of the hip joint. Therefore, this in vitro study examined the presence and differentiation potential of MSCs isolated from the bone marrow, arthritic hyaline cartilage, the LCF and full-thickness samples of the anterior joint capsule of the hip joint. METHODS MSCs were isolated and multiplied in adherent monolayer cell cultures. Osteogenesis and adipogenesis were induced in monolayer cell cultures for 21 days using a differentiation medium containing specific growth factors, while chondrogenesis in the presence of TGF-ß1 was performed using pellet-culture for 27 days. Control cultures were maintained for comparison over the same duration of time. The differentiation process was analyzed using histological and immunohistochemical stainings as well as semiquantitative RT-PCR for measuring the mean expression levels of tissue-specific genes. RESULTS This in vitro research showed that the isolated cells from all four donor tissues grew plastic-adherent and showed similar adipogenic and osteogenic differentiation capacity as proven by the histological detection of lipid droplets or deposits of extracellular calcium and collagen type I. After 27 days of chondrogenesis proteoglycans accumulated in the differentiated MSC-pellets from all donor tissues. Immunohistochemical staining revealed vast amounts of collagen type II in all differentiated MSC-pellets, except for those from the LCF. Interestingly, all differentiated MSCs still showed a clear increase in mean expression of adipogenic, osteogenic and chondrogenic marker genes. In addition, the examination of an exemplary selected donor sample revealed that cells from all four donor tissues were clearly positive for the surface markers CD44, CD73, CD90 and CD105 by flow cytometric analysis. CONCLUSIONS This study proved the presence of MSC-like cells in all four examined donor tissues of the hip joint. No significant differences were observed during osteogenic or adipogenic differentiation depending on the source of MSCs used. Further research is necessary to fully determine the tripotent differentiation potential of cells isolated from the LCF and capsule tissue of the hip joint.
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Affiliation(s)
- Mike Wagenbrenner
- Department of Orthopaedic Surgery, University of Wuerzburg, Koenig-Ludwig-Haus, Brettreichstr. 11, 97074, Wuerzburg, Germany
| | - Tizian Heinz
- Department of Orthopaedic Surgery, University of Wuerzburg, Koenig-Ludwig-Haus, Brettreichstr. 11, 97074, Wuerzburg, Germany
| | - Konstantin Horas
- Department of Orthopaedic Surgery, University of Wuerzburg, Koenig-Ludwig-Haus, Brettreichstr. 11, 97074, Wuerzburg, Germany
| | - Axel Jakuscheit
- Department of Orthopaedic Surgery, University of Wuerzburg, Koenig-Ludwig-Haus, Brettreichstr. 11, 97074, Wuerzburg, Germany
| | - Joerg Arnholdt
- Department of Orthopaedic Surgery, University of Wuerzburg, Koenig-Ludwig-Haus, Brettreichstr. 11, 97074, Wuerzburg, Germany
| | - Marietta Herrmann
- Bernhard-Heine-Center for Locomotion Research, University of Wuerzburg, Wuerzburg, Germany.,IZKF Research Group Tissue Regeneration in Musculoskeletal Disease, University Clinics Wuerzburg, Wuerzburg, Germany
| | - Maximilian Rudert
- Department of Orthopaedic Surgery, University of Wuerzburg, Koenig-Ludwig-Haus, Brettreichstr. 11, 97074, Wuerzburg, Germany
| | - Boris M Holzapfel
- Department of Orthopaedic Surgery, University of Wuerzburg, Koenig-Ludwig-Haus, Brettreichstr. 11, 97074, Wuerzburg, Germany
| | - Andre F Steinert
- Department of Orthopaedic, Trauma, Shoulder and Arthroplasty Surgery, Rhön-Klinikum Campus Bad Neustadt, Von-Guttenberg-Str. 11, 97616, Bad Neustadt, Germany
| | - Manuel Weißenberger
- Department of Orthopaedic Surgery, University of Wuerzburg, Koenig-Ludwig-Haus, Brettreichstr. 11, 97074, Wuerzburg, Germany.
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37
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Expression and function of cartilage-derived pluripotent cells in joint development and repair. Stem Cell Res Ther 2020; 11:111. [PMID: 32160923 PMCID: PMC7066750 DOI: 10.1186/s13287-020-01604-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 02/11/2020] [Accepted: 02/14/2020] [Indexed: 02/08/2023] Open
Abstract
Cartilage-derived pluripotent cells reside in hyaline cartilage and fibrocartilage. These cells have the potential for multidirectional differentiation; can undergo adipogenesis, osteogenesis, and chondrogenesis; and have been classified as mesenchymal stem cells (MSCs) conforming to the minimal criteria of the International Society for Cellular Therapy. Cartilage tissue is prone to injury and is difficult to repair. As cartilage-derived pluripotent cells are the closest cell source to cartilage tissue, they are expected to have the strongest ability to differentiate into cartilage compared to other MSCs. This review focuses on the organizational distribution, expression, and function of cartilage-derived pluripotent cells in joint development and repair to help explore the therapeutic potential of in situ cartilage-derived pluripotent cells for joint cartilage repair.
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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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Chen D, Kim DJ, Shen J, Zou Z, O'Keefe RJ. Runx2 plays a central role in Osteoarthritis development. J Orthop Translat 2019; 23:132-139. [PMID: 32913706 PMCID: PMC7452174 DOI: 10.1016/j.jot.2019.11.008] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 11/21/2019] [Accepted: 11/25/2019] [Indexed: 12/20/2022] Open
Abstract
Osteoarthritis (OA) is the most common form of arthritis, is the leading cause of impaired mobility in the elderly, and accounts for more than a third of chronic moderate to severe pain. As a degenerative joint disorder, OA affects the whole joint and results in synovial hyperplasia, degradation of articular cartilage, subchondral sclerosis, osteophyte formation, and chronic pain. Currently, there is no effective drug to decelerate OA progression and molecular targets for drug development have been insufficiently investigated. Anti-OA drug development can benefit from more and precise knowledge of molecular targets for drug development. Runt-related transcription factor 2 (Runx2) is a key transcription factor controlling osteoblast and chondrocyte differentiation and is among the most promising potential therapeutic targets. Notably, Runx2 expression is upregulated in several murine OA models, suggesting a role in disease pathogenesis. In this review article, we summarized recent findings on Runx2 related to OA development and evaluated its potential as a therapeutic target. The translational potential of this article A better understanding of the role of Runx2 in osteoarthritis pathogenesis will contribute to the development of novel intervention of osteoarthritis disease.
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Affiliation(s)
- Di Chen
- Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Dongyeon J Kim
- Department of Orthopedic Surgery, Washington University at St. Louis, MO, USA
| | - Jie Shen
- Department of Orthopedic Surgery, Washington University at St. Louis, MO, USA
| | - Zhen Zou
- Department of Orthopedic Surgery, Washington University at St. Louis, MO, USA
| | - Regis J O'Keefe
- Department of Orthopedic Surgery, Washington University at St. Louis, MO, USA
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Mantripragada VP, Bova WA, Piuzzi NS, Boehm C, Obuchowski NA, Midura RJ, Muschler GF. Native-Osteoarthritic Joint Resident Stem and Progenitor Cells for Cartilage Cell-Based Therapies: A Quantitative Comparison With Respect to Concentration and Biological Performance. Am J Sports Med 2019; 47:3521-3530. [PMID: 31671273 DOI: 10.1177/0363546519880905] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Cell-based therapy for cartilage repair is a promising approach and is becoming an established technique. Yet, there is no consensus on the optimal cell source. PURPOSE To provide a donor-matched quantitative comparison of the connective tissue progenitors (CTPs) derived from cartilage (Outerbridge grade 1-3 [G1-2-3]), bone marrow aspirate concentrate (BMC), infrapatellar fat pad (IPFP), synovium, and periosteum with respect to (1) cell concentration ([Cell], cells/mL), (2) CTP prevalence (PCTP, colonies per million cells), and (3) biological performance based on in vitro proliferation potential (cells per colony) colony density, and differentiation potential (expression of negatively charged extracellular matrix: glycosaminoglycan-rich extra cellular matrix [GAG-ECM]). STUDY DESIGN Descriptive laboratory study. METHODS Tissues were obtained from 10 patients undergoing total knee arthroplasty (mean age, 59 years; women, n = 6). Automated quantitative colony-forming unit analysis was used to compare [Cell], PCTP, and CTP biological performance across tissue sources. RESULTS [Cell] was highest in grade 3 cartilage (P = .002) and BMC (P = .001). Median PCTP was highest in IPFP (P = .001), synovium (P = .003), and G1-2 cartilage (P = .02). Proliferation was highest in synovium-derived CTPs (P < .001). Median colony density was highest in G1-2-3 (P < .001). Median GAG-ECM was highest in G1-2-3 (P < .001). Within each patient, CTPs derived from all tissues were highly heterogeneous in biological performance as determined by cells per colony, density, and GAG-ECM. CONCLUSION Tissue sources differ in [Cell], PCTP, and biological attributes. The data presented in this study suggest that cartilage (G1-2-3) is the preferred tissue source for cartilage repair based on PCTP and GAG-ECM, followed by synovium, IPFP, BMC, and periosteum. However, due to the heterogeneous mixture of CTPs within each tissue source, there exists a subset of CTPs with biological performance similar to G1-2-3 cartilage, particularly in synovium and IPFP. Performance-based clonal selection and expansion of preferred CTPs and their progeny will potentially lead to improved cell population with predictive future. CLINICAL RELEVANCE Optimal tissue regeneration strategies will require informed decisions regarding which of the available tissue sources to use. Optimizing cell sourcing in any tissue may require separation of CTPs with preferred attributes from those with less desirable attributes. The heterogeneity manifest in the early stage of colony formation represents an opportunity for performance-based clone selection for clinical cell processing and manufacturing.
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Affiliation(s)
- Venkata P Mantripragada
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Wes A Bova
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Nicolas S Piuzzi
- Department of Orthopedic Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | - Cynthia Boehm
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Nancy A Obuchowski
- Department of Quantitative Health Science, Cleveland Clinic, Cleveland, Ohio, USA
| | - Ronald J Midura
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - George F Muschler
- Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Orthopedic Surgery, Cleveland Clinic, Cleveland, Ohio, USA
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He S, Ruan D, Chen Y, Ran J, Chen X, Yin Z, Tang C, Huang J, Heng BC, Chen J, Chen W, Shen W, Ouyang H. Characterization and Comparison of Postnatal Rat Meniscus Stem Cells at Different Developmental Stages. Stem Cells Transl Med 2019; 8:1318-1329. [PMID: 31638337 PMCID: PMC6877772 DOI: 10.1002/sctm.19-0125] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 09/24/2019] [Indexed: 11/25/2022] Open
Abstract
Meniscus‐derived stem cells (MeSCs) are a potential cell source for meniscus tissue engineering. The stark morphological and structural changes of meniscus tissue during development indicate the complexity of MeSCs at different tissue regions and stages of development. In this study, we characterized and compared postnatal rat meniscus tissue and MeSCs at different tissue regions and stages of development. We observed that the rat meniscus tissue exhibited marked changes in tissue morphology during development, with day 7 being the most representative time point of different developmental stages. All rat MeSCs displayed typical stem cell characteristics. Rat MeSCs derived from day 7 inner meniscus tissue exhibited the highest self‐renewal capacity, cell proliferation, differentiation potential toward various mesenchymal lineage and the highest expression levels of chondrogenic genes and proteins. Transplantation of rat MeSCs derived from day 7 inner meniscus tissue promoted neo‐tissue formation and effectively protected joint surface cartilage in vivo. Our results demonstrated for the first time that rat MeSCs are not necessarily better at earlier developmental stages, and that rat MeSCs derived from day 7 inner meniscus tissue may be a superior cell source for effective meniscus regeneration and articular cartilage protection. This information could make a significant contribution to human meniscus tissue engineering in the future. stem cells translational medicine2019;8:1318&1329 (A): Meniscus tissue at different tissue regions and stages of development. (B): MeSCs at different tissue regions and stages of development. (C): Intra‐articular injection of MeSCs for meniscus regeneration and OA suppression. *Significant difference between two groups at p < .05. **Significant difference between two groups at p < .01. ***Significant difference between two groups at p < .001. ****Significant difference between two groups at p < .0001. N.S., No significant difference between two groups at p ≥ .05.![]()
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Affiliation(s)
- Shaoqi He
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.,Department of Orthopedic Surgery, Third Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Dengfeng Ruan
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Yangwu Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jisheng Ran
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.,Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Xiao Chen
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Zi Yin
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Chenqi Tang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jiayun Huang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Boon Chin Heng
- Peking University School of Stomatology, Beijing, People's Republic of China
| | - Jialin Chen
- School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Weishan Chen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.,Department of Orthopedics, Research Institute of Zhejiang University, Hangzhou, People's Republic of China
| | - Weiliang Shen
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.,Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.,Department of Orthopedics, Research Institute of Zhejiang University, Hangzhou, People's Republic of China.,China Orthopaedic Regenerative Medicine (CORMed), Hangzhou, People's Republic of China
| | - Hongwei Ouyang
- Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.,China Orthopaedic Regenerative Medicine (CORMed), Hangzhou, People's Republic of China
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42
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Zheng W, Gu X, Sun X, Hu D. Effects of hypoxia‑inducible factor‑1α on the proliferation and apoptosis of human synovial mesenchymal stem cells. Mol Med Rep 2019; 20:4315-4322. [PMID: 31545415 DOI: 10.3892/mmr.2019.10656] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 08/19/2019] [Indexed: 11/05/2022] Open
Abstract
Hypoxia is a constant feature of the synovial microenvironment. How synovial mesenchymal stem cells (SMSCs) proliferate and differentiate in a hypoxic environment over a long period of time has aroused the interest of researchers. The aim of the present study was to explore the effects of hypoxia‑inducible factor‑1α (HIF‑1α) on the proliferation and apoptosis of human SMSCs. SMSCs were harvested and cultured under different concentration of oxygen, normoxia (21% O2), hypoxia (5% O2) and severe hypoxia (0.5% O2) to determine its effect on the expression of HIF‑1α. Then, the cells were collected and cell proliferation and apoptosis were detected at severe hypoxia (0.5% O2) and hypoxia (5% O2) conditions following HIF‑1α siRNA transfection. There were no significant changes in cellular proliferation or apoptosis when cultured in normoxia (21% O2), hypoxia (5% O2) or severe hypoxia (0.5% O2). However, the mRNA and protein expression of HIF‑1α were markedly upregulated in the hypoxic conditions. Further experiments suggested that the proliferation of SMSCs was obviously suppressed and apoptosis was markedly increased under severe hypoxic (0.5%) and hypoxic (5% O2) conditions following HIF‑1α siRNA transfection. In conclusion, HIF‑1α effectively improved the tolerance of SMSCs to hypoxia, which may promote cellular proliferation and prevent the apoptosis of SMSCs under hypoxic conditions.
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Affiliation(s)
- Weiwei Zheng
- Department of Orthopaedics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215008, P.R. China
| | - Xueping Gu
- Department of Orthopaedics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215008, P.R. China
| | - Xingwei Sun
- Department of Intervention, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China
| | - Dan Hu
- Department of Orthopaedics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, Jiangsu 215008, P.R. China
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Jiang LF, Fang JH, Wu LD. Role of infrapatellar fat pad in pathological process of knee osteoarthritis: Future applications in treatment. World J Clin Cases 2019; 7:2134-2142. [PMID: 31531309 PMCID: PMC6718789 DOI: 10.12998/wjcc.v7.i16.2134] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 06/11/2019] [Accepted: 06/27/2019] [Indexed: 02/05/2023] Open
Abstract
It has been found that obese people have a higher proportion in suffering from osteoarthritis (OA), not only in the weight-bearing joints like knee and hip joints, even in non-weight-bearing joints such as hand joints. One of the reasons is because the large amount of adipose tissue secretes some factors, which can promote the occurrence of arthritis. As an important structure of the knee joint, the infrapatellar fat pad (IPFP) is actually a piece of adipose tissue. The aim of this review is to offer a comprehensive view of the anatomy and physiological characteristics of IPFP and its relationship with the pathological process of OA, indicating the important function of IPFP in OA. At the same time, with the development of adipose derived stem cells in the treatment of OA, owing to its special advantages, the IPFP is becoming a kind of important, minimally invasive fat stem cell source, providing a new approach for the treatment of OA. We hope that this review will offer an overview of all published data regarding the IPFP and will indicate novel directions for future research.
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Affiliation(s)
- Li-Feng Jiang
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Jing-Hua Fang
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Li-Dong Wu
- Department of Orthopedics Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
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Kondo S, Nakagawa Y, Mizuno M, Katagiri K, Tsuji K, Kiuchi S, Ono H, Muneta T, Koga H, Sekiya I. Transplantation of Aggregates of Autologous Synovial Mesenchymal Stem Cells for Treatment of Cartilage Defects in the Femoral Condyle and the Femoral Groove in Microminipigs. Am J Sports Med 2019; 47:2338-2347. [PMID: 31306591 DOI: 10.1177/0363546519859855] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Previous work has demonstrated that patients with cartilage defects of the knee benefit from arthroscopic transplantation of autologous synovial mesenchymal stem cells (MSCs) in terms of magnetic resonance imaging (MRI), qualitative histologic findings, and Lysholm score. However, the effectiveness was limited by the number of cells obtained, so large-sized defects (>500 mm2) were not investigated. The use of MSC aggregates may enable treatment of larger defects by increasing the number of MSCs adhering to the cartilage defect. PURPOSE To investigate whether transplantation of aggregates of autologous synovial MSCs with 2-step surgery could promote articular cartilage regeneration in microminipig osteochondral defects. STUDY DESIGN Controlled laboratory study. METHODS Synovial MSCs derived from a microminipig were examined for in vitro colony-forming and multidifferentiation abilities. An aggregate of 250,000 synovial MSCs was formed with hanging drop culture, and 16 aggregates (for each defect) were implanted on both osteochondral defects (6 × 6 × 1.5 mm) created in the medial femoral condyle and femoral groove (MSC group). The defects in the contralateral knee were left empty (control group). The knee joints were evaluated at 4 and 12 weeks by macroscopic findings and histology. MRI T1rho mapping images were acquired at 12 weeks. For cell tracking, synovial MSCs were labeled with ferucarbotran before aggregate formation and were observed with MRI at 1 week. RESULTS Synovial MSCs showed in vitro colony-forming and multidifferentiation abilities. Regenerative cartilage formation was significantly better in the MSC group than in the control group, as indicated by International Cartilage Repair Society score (macro), modified Wakitani score (histology), and T1rho mapping (biochemical MRI) in the medial condyle at 12 weeks. Implanted cells, labeled with ferucarbotran, were observed in the osteochondral defects at 1 week with MRI. No significant difference was noted in the modified Wakitani score at 4 weeks in the medial condyle and at 4 and 12 weeks in the femoral groove. CONCLUSION Transplantation of autologous synovial MSC aggregates promoted articular cartilage regeneration at the medial femoral condyle at 12 weeks in microminipigs. CLINICAL RELEVANCE Aggregates of autologous synovial MSCs could expand the indications for cartilage repair with synovial MSCs.
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Affiliation(s)
- Shimpei Kondo
- Department of Joint Surgery and Sports Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yusuke Nakagawa
- Department of Joint Surgery and Sports Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.,Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Mitsuru Mizuno
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kenta Katagiri
- Department of Joint Surgery and Sports Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kunikazu Tsuji
- Department of Cartilage Regeneration, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | | | | | - Takeshi Muneta
- National Hospital Organization Disaster Medical Center, Tokyo, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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45
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Qu D, Zhu JP, Childs HR, Lu HH. Nanofiber-based transforming growth factor-β3 release induces fibrochondrogenic differentiation of stem cells. Acta Biomater 2019; 93:111-122. [PMID: 30862549 DOI: 10.1016/j.actbio.2019.03.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 03/06/2019] [Accepted: 03/07/2019] [Indexed: 12/21/2022]
Abstract
Fibrocartilage is typically found in regions subject to complex, multi-axial loads and plays a critical role in musculoskeletal function. Mesenchymal stem cell (MSC)-mediated fibrocartilage regeneration may be guided by administration of appropriate chemical and/or physical cues, such as by culturing cells on polymer nanofibers in the presence of the chondrogenic growth factor TGF-β3. However, targeted delivery and maintenance of effective local factor concentrations remain challenges for implementation of growth factor-based regeneration strategies in clinical settings. Thus, the objective of this study was to develop and optimize the bioactivity of a biomimetic nanofiber scaffold system that enables localized delivery of TGF-β3. To this end, we fabricated TGF-β3-releasing nanofiber meshes that provide sustained growth factor delivery and demonstrated their potential for guiding synovium-derived stem cell (SDSC)-mediated fibrocartilage regeneration. TGF-β3 delivery enhanced cell proliferation and synthesis of relevant fibrocartilaginous matrix in a dose-dependent manner. By designing a scaffold that eliminates the need for exogenous or systemic growth factor administration and demonstrating that fibrochondrogenesis requires a lower growth factor dose compared to previously reported, this study represents a critical step towards developing a clinical solution for regeneration of fibrocartilaginous tissues. STATEMENT OF SIGNIFICANCE: Fibrocartilage is a tissue that plays a critical role throughout the musculoskeletal system. However, due to its limited self-healing capacity, there is a significant unmet clinical need for more effective approaches for fibrocartilage regeneration. We have developed a nanofiber-based scaffold that provides both the biomimetic physical cues, as well as localized delivery of the chemical factors needed to guide stem cell-mediated fibrocartilage formation. Specifically, methods for fabricating TGF-β3-releasing nanofibers were optimized, and scaffold-mediated TGF-β3 delivery enhanced cell proliferation and synthesis of fibrocartilaginous matrix, demonstrating for the first time, the potential for nanofiber-based TGF-β3 delivery to guide stem cell-mediated fibrocartilage regeneration. This nanoscale delivery platform represents an exciting new strategy for fibrocartilage regeneration.
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Affiliation(s)
- Dovina Qu
- Biomaterials and Interface Tissue Engineering Laboratory, Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace Building, MC 8904, 1210 Amsterdam Avenue, New York, NY 10027, United States
| | - Jennifer P Zhu
- Biomaterials and Interface Tissue Engineering Laboratory, Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace Building, MC 8904, 1210 Amsterdam Avenue, New York, NY 10027, United States
| | - Hannah R Childs
- Biomaterials and Interface Tissue Engineering Laboratory, Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace Building, MC 8904, 1210 Amsterdam Avenue, New York, NY 10027, United States
| | - Helen H Lu
- Biomaterials and Interface Tissue Engineering Laboratory, Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace Building, MC 8904, 1210 Amsterdam Avenue, New York, NY 10027, United States.
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Huang J, Zhao L, Fan Y, Liao L, Ma PX, Xiao G, Chen D. The microRNAs miR-204 and miR-211 maintain joint homeostasis and protect against osteoarthritis progression. Nat Commun 2019; 10:2876. [PMID: 31253842 PMCID: PMC6599052 DOI: 10.1038/s41467-019-10753-5] [Citation(s) in RCA: 126] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 05/24/2019] [Indexed: 12/19/2022] Open
Abstract
Osteoarthritis (OA) is a common, painful disease. Currently OA is incurable, and its etiology largely unknown, partly due to limited understanding of OA as a whole-joint disease. Here we report that two homologous microRNAs, miR-204 and miR-211, maintain joint homeostasis to suppress OA pathogenesis. Specific knockout of miR-204/-211 in mesenchymal progenitor cells (MPCs) results in Runx2 accumulation in multi-type joint cells, causing whole-joint degeneration. Specifically, miR-204/-211 loss-of-function induces matrix-degrading proteases in articular chondrocytes and synoviocytes, stimulating articular cartilage destruction. Moreover, miR-204/-211 ablation enhances NGF expression in a Runx2-dependent manner, and thus hyper-activates Akt signaling and MPC proliferation, underlying multiplex non-cartilaginous OA conditions including synovial hyperplasia, osteophyte outgrowth and subchondral sclerosis. Importantly, miR-204/-211-deficiency-induced OA is largely rescued by Runx2 insufficiency, confirming the miR-204/-211-Runx2 axis. Further, intraarticular administration of miR-204-expressing adeno-associated virus significantly decelerates OA progression. Collectively, miR-204/-211 are essential in maintaining healthy homeostasis of mesenchymal joint cells to counteract OA pathogenesis. Osteoarthritis involves whole-joint tissue degeneration. Here, the authors show that miR-204 and miR-211 in mesenchymal joint cells regulate their proliferation, catabolic and osteogenic responses, and that disease progression is ameliorated by intra-articular miR-204 delivery in mice.
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Affiliation(s)
- Jian Huang
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Lan Zhao
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Yunshan Fan
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Lifan Liao
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Peter X Ma
- Department of Biologic and Materials Science, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Guozhi Xiao
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, 60612, USA
| | - Di Chen
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, 60612, USA.
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Negi H, Takeuchi S, Kamei N, Yanada S, Adachi N, Ochi M. In Vitro Safety and Quality of Magnetically Labeled Human Mesenchymal Stem Cells Preparation for Cartilage Repair. Tissue Eng Part C Methods 2019; 25:324-333. [PMID: 31002015 DOI: 10.1089/ten.tec.2019.0001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
IMPACT STATEMENT This study is very important for a preclinical assessment of the safety and quality of magnetically labeled mesenchymal stem cells (MSCs) for use in cartilage repair. The findings of this study show that magnetic labeling with an appropriate density of magnetic particles has no harmful effects on the safety and quality of MSCs.
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Affiliation(s)
- Hiroshi Negi
- 1 Department of Orthopaedic Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | | | - Naosuke Kamei
- 1 Department of Orthopaedic Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,3 Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan
| | | | - Nobuo Adachi
- 1 Department of Orthopaedic Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Mitsuo Ochi
- 4 Hiroshima University, Higashihiroshima, Japan
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Abdal Dayem A, Lee SB, Kim K, Lim KM, Jeon TI, Seok J, Cho ASG. Production of Mesenchymal Stem Cells Through Stem Cell Reprogramming. Int J Mol Sci 2019; 20:ijms20081922. [PMID: 31003536 PMCID: PMC6514654 DOI: 10.3390/ijms20081922] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 04/10/2019] [Accepted: 04/15/2019] [Indexed: 12/26/2022] Open
Abstract
Mesenchymal stem cells (MSCs) possess a broad spectrum of therapeutic applications and have been used in clinical trials. MSCs are mainly retrieved from adult or fetal tissues. However, there are many obstacles with the use of tissue-derived MSCs, such as shortages of tissue sources, difficult and invasive retrieval methods, cell population heterogeneity, low purity, cell senescence, and loss of pluripotency and proliferative capacities over continuous passages. Therefore, other methods to obtain high-quality MSCs need to be developed to overcome the limitations of tissue-derived MSCs. Pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are considered potent sources for the derivation of MSCs. PSC-derived MSCs (PSC-MSCs) may surpass tissue-derived MSCs in proliferation capacity, immunomodulatory activity, and in vivo therapeutic applications. In this review, we will discuss basic as well as recent protocols for the production of PSC-MSCs and their in vitro and in vivo therapeutic efficacies. A better understanding of the current advances in the production of PSC-MSCs will inspire scientists to devise more efficient differentiation methods that will be a breakthrough in the clinical application of PSC-MSCs.
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Affiliation(s)
- Ahmed Abdal Dayem
- Department of Stem Cell & Regenerative Biotechnology, Incurable Disease Animal Model and Stem Cell Institute (IDASI), Konkuk University, Gwangjin-gu, Seoul 05029, Korea.
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Chin S, Furukawa KI, Kurotaki K, Nagasaki S, Wada K, Kumagai G, Motomura S, Ishibashi Y. Facilitation of Chemotaxis Activity of Mesenchymal Stem Cells via Stromal Cell-Derived Factor-1 and Its Receptor May Promote Ectopic Ossification of Human Spinal Ligaments. J Pharmacol Exp Ther 2019; 369:1-8. [PMID: 30692148 DOI: 10.1124/jpet.118.254367] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 01/18/2019] [Indexed: 03/08/2025] Open
Abstract
Mesenchymal stem cells (MSCs) have been used to elucidate the pathogenesis of numerous diseases. Our recent study showed that MSCs may conduce to the ossification of spinal ligaments. Stromal cell-derived factor-1 (SDF-1) and CXC chemokine receptor 4 (CXCR4) regulate MSC migration. Moreover, their expression is elevated in sites of damage and remodeling in pathologic states. We explored the possible role of the SDF-1/CXCR4 axis in the chemotactic behavior of MSCs in the ossification of spinal ligaments. Specimens of thoracic vertebra ossified ligamentum flavum (OLF) and non-OLF plaques were received from patients in whom we had performed spine surgery. Paraffin-embedded tissue sections were prepared for immunohistochemical staining. Cultured MSCs from the ligamentum flavum were prepared for in vitro analyses. We observed SDF-1 and CXCR4 localization immunohistochemically in the perivascular area and collagenous matrix of ligaments and in chondrocytes near the ossification front of OLF. And then, immunohistochemical staining showed a close relationship between MSCs and the SDF-1/CXCR4 axis. In the in vitro analyses, expression of the SDF-1/CXCR4 and the migratory capacity of MSCs in OLF were remarkably higher compared with non-OLF MSCs. Furthermore, the migration of MSCs was upregulated by SDF-1 and downregulated by treatment with AMD3100 (C28H54N88HCl), a specific antagonist for CXCR4. All in vitro test data showed a significant difference in MSCs from OLF compared with non-OLF MSCs. Our results reveal that the SDF-1/CXCR4 axis may contribute to an MSC-mediated increase in the ossification process, indicating that the SDF-1/CXCR4 axis may become a potential target for a novel therapeutic strategy for ossification of spinal ligaments.
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Affiliation(s)
- Shunfu Chin
- Departments of Orthopaedic Surgery (S.C., K.W., G.K., Y.I.) and Pharmacology (K.-I.F., K.K., S.N., S.M.), Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori, Japan
| | - Ken-Ichi Furukawa
- Departments of Orthopaedic Surgery (S.C., K.W., G.K., Y.I.) and Pharmacology (K.-I.F., K.K., S.N., S.M.), Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori, Japan
| | - Keigo Kurotaki
- Departments of Orthopaedic Surgery (S.C., K.W., G.K., Y.I.) and Pharmacology (K.-I.F., K.K., S.N., S.M.), Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori, Japan
| | - Shunpei Nagasaki
- Departments of Orthopaedic Surgery (S.C., K.W., G.K., Y.I.) and Pharmacology (K.-I.F., K.K., S.N., S.M.), Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori, Japan
| | - Kanichiro Wada
- Departments of Orthopaedic Surgery (S.C., K.W., G.K., Y.I.) and Pharmacology (K.-I.F., K.K., S.N., S.M.), Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori, Japan
| | - Gentaro Kumagai
- Departments of Orthopaedic Surgery (S.C., K.W., G.K., Y.I.) and Pharmacology (K.-I.F., K.K., S.N., S.M.), Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori, Japan
| | - Shigeru Motomura
- Departments of Orthopaedic Surgery (S.C., K.W., G.K., Y.I.) and Pharmacology (K.-I.F., K.K., S.N., S.M.), Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori, Japan
| | - Yasuyuki Ishibashi
- Departments of Orthopaedic Surgery (S.C., K.W., G.K., Y.I.) and Pharmacology (K.-I.F., K.K., S.N., S.M.), Graduate School of Medicine, Hirosaki University, Hirosaki, Aomori, Japan
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Treatment of Knee Meniscus Pathology: Rehabilitation, Surgery, and Orthobiologics. PM R 2019; 11:292-308. [DOI: 10.1016/j.pmrj.2018.08.384] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 08/11/2018] [Indexed: 01/13/2023]
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