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Liu M, Wu C, Wu C, Zhou Z, Fang R, Liu C, Ning R. Immune cells differentiation in osteoarthritic cartilage damage: friends or foes? Front Immunol 2025; 16:1545284. [PMID: 40201177 PMCID: PMC11975574 DOI: 10.3389/fimmu.2025.1545284] [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: 12/14/2024] [Accepted: 03/07/2025] [Indexed: 04/10/2025] Open
Abstract
Osteoarthritis (OA) is a chronic disease primarily characterized by degenerative changes in articular cartilage and synovitis, for which there are currently no targeted or curative therapies available in clinical practice. In recent years, the in-depth analysis of OA using single-cell sequencing and immunomics technologies has revealed the presence of multiple immune cell subsets, as well as different differentiation states within the same subset, in OA. Through immune-immune and immune-joint tissue interactions, these cells collectively promote or inhibit the progression of arthritis. This complex immune network, where "friends and foes coexist," has made targeted therapeutic strategies aimed at directly eliminating immune cells challenging, highlighting the urgent need for a detailed review of the composition, distribution, functional heterogeneity, therapeutic potential, and potential risks of immune subsets within the joint. Additionally, the similarities and differences between OA and rheumatoid arthritis (RA) in terms of diagnosis and immunotherapy need to be precisely understood, in order to draw lessons from or reject RA-based immunotherapies. To this end, this review summarizes the major triggers of inflammation in OA, the differentiation characteristics of key immune cell subsets, and compares the similarities and differences between OA and RA in diagnosis and treatment. It also outlines the current immunomodulatory strategies for OA and their limitations. Furthermore, we provide a detailed and focused discussion on immune cells that act as "friends or foes" in arthritis, covering the M1/M2 polarization of macrophages, functional heterogeneity of neutrophils, unique roles of dendritic cells at different maturation states, the balance between pro-inflammatory T cells and regulatory T cells (Tregs), and the diverse functions of B cells, plasma cells, and regulatory B cells (Bregs) in OA. By interpreting the roles of these immune cells, this review clarifies the dynamic changes and interactions of immune cells in OA joints, providing a theoretical foundation for more precise targeted interventions in future clinical practice.
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Affiliation(s)
| | | | | | | | | | - Chenfeng Liu
- Department of Orthopedics, The Third Affiliated Hospital of Anhui Medical University (The First People’s Hospital of Hefei), School of Life Science, Anhui Medical University, Hefei, Anhui, China
| | - Rende Ning
- Department of Orthopedics, The Third Affiliated Hospital of Anhui Medical University (The First People’s Hospital of Hefei), School of Life Science, Anhui Medical University, Hefei, Anhui, China
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Ramzan F, Salim A, Hussain A, Khan I. Unleashing the Healing Power of Mesenchymal Stem Cells for Osteochondral Abnormalities. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2024. [DOI: 10.1007/s40883-024-00356-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 07/25/2024] [Accepted: 08/31/2024] [Indexed: 01/11/2025]
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Wang P, Zhao Z, Li Z, Li X, Huang B, Lu X, Dai S, Li S, Man Z, Li W. Attenuation of osteoarthritis progression via locoregional delivery of Klotho-expressing plasmid DNA and Tanshinon IIA through a stem cell-homing hydrogel. J Nanobiotechnology 2024; 22:325. [PMID: 38858695 PMCID: PMC11163801 DOI: 10.1186/s12951-024-02608-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 05/30/2024] [Indexed: 06/12/2024] Open
Abstract
BACKGROUND Osteoarthritis (OA) is an aging-related degenerative joint disorder marked by joint discomfort and rigidity. Senescent chondrocytes release pro-inflammatory cytokines and extracellular matrix-degrading proteins, creating an inflammatory microenvironment that hinders chondrogenesis and accelerates matrix degradation. Targeting of senescent chondrocytes may be a promising approach for the treatment of OA. Herein, we describe the engineering of an injectable peptide-hydrogel conjugating a stem cell-homing peptide PFSSTKT for carrying plasmid DNA-laden nanoparticles and Tanshinon IIA (pPNP + TIIA@PFS) that was designed to attenuate OA progression by improving the senescent microenvironment and fostering cartilage regeneration. RESULTS Specifically, pPNP + TIIA@PFS elevates the concentration of the anti-aging protein Klotho and blocks the transmission of senescence signals to adjacent healthy chondrocytes, significantly mitigating chondrocyte senescence and enhancing cartilage integrity. Additionally, pPNP + TIIA@PFS recruit bone mesenchymal stem cells and directs their subsequent differentiation into chondrocytes, achieving satisfactory chondrogenesis. In surgically induced OA model rats, the application of pPNP + TIIA@PFS results in reduced osteophyte formation and attenuation of articular cartilage degeneration. CONCLUSIONS Overall, this study introduces a novel approach for the alleviation of OA progression, offering a foundation for potential clinical translation in OA therapy.
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Affiliation(s)
- Peng Wang
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, P. R. China
| | - Zhibo Zhao
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, P. R. China
| | - Ziyang Li
- Department of Orthopedic Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiao Li
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, P. R. China
| | - Benzhao Huang
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China
| | - Xiaoqing Lu
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China
| | - Shimin Dai
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China
| | - Shishuo Li
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China
| | - Zhentao Man
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, P. R. China.
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China.
- College of Sports Medicine and Rehabilitation, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, P. R. China.
- Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250062, P. R. China.
| | - Wei Li
- Department of Joint Surgery, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, P. R. China.
- Department of Joint Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, P. R. China.
- College of Sports Medicine and Rehabilitation, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250021, P. R. China.
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Fu Y, Zhang C, Yang Y, Zhou B, Yang M, Zhu G, Zhu Y. Effect of umbilical cord blood-mononuclear cells on knee osteoarthritis in rabbits. J Orthop Surg Res 2024; 19:323. [PMID: 38811966 PMCID: PMC11138004 DOI: 10.1186/s13018-024-04815-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 05/27/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND To investigate the effect and underlying mechanism of umbilical cord blood-mononuclear cells (UCB-MNCs) in treating knee osteoarthritis (KOA) in rabbits. METHODS A rabbit KOA model was prepared by anterior cruciate ligament transection (ACLT). Fifty New Zealand white rabbits were randomly divided into the control group, model group, sodium hyaluronate (SH) group, platelet-rich plasma (PRP) group and UCB-MNC group. Knee injections were performed once a week for five consecutive weeks. The gross view of the knee joint, morphology of knee cartilage and structural changes in the knee joint were observed on CT scans, and graded by the Lequesne MG behavioral score and the Mankin score. TNF-α and IL-1β levels in the synovial fluid of the knee were measured by the enzyme-linked immunosorbent assay (ELISA). Expression levels of MMP-13 and COL-II in the knee cartilage were detected by Western blotting and qRT-PCR. RESULTS The Lequesne MG behavioral score and the Mankin score were significantly higher in the model group than those in the control group (P < 0.05). Rabbits in the SH, PRP and UCB-MNC groups had sequentially lower scores than those in the model group. Imaging features of KOA were more pronounced in the model group than in the remaining groups. CB-MNC significantly relieved KOA, compared to SH and PRP. Significantly higher levels of TNF-α and IL-1β in the synovial fluid of the knee, and up-regulated MMP-13 and down-regulated COL-II in the knee cartilage were detected in the model group than in the control group. These changes were significantly reversed by the treatment with SH, PRP and UCB-MNCs, especially UCB-MNCs. CONCLUSION Injections of UCB-MNCs into knees protect the articular cartilage and hinder the progression of KOA in rabbits by improving the local microenvironment at knee joints.
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Affiliation(s)
- Yuhang Fu
- The Second School of Clinical Medicine of Binzhou Medical University, Yantai, 264199, Shandong Province, China
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China
| | - Chi Zhang
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China
| | - Yong Yang
- Yantai City Yantai Mountain Hospital, Yantai, 264008, Shandong Province, China
| | - Baisui Zhou
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China
| | - Meng Yang
- The Second School of Clinical Medicine of Binzhou Medical University, Yantai, 264199, Shandong Province, China
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China
| | - Guoshuai Zhu
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China
| | - Yonglin Zhu
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264199, Shandong Province, China.
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Li PL, Chen DF, Li XT, Hao RC, Zhao ZD, Li ZL, Yin BF, Tang J, Luo YW, Wu CT, Nie JJ, Zhu H. Microgel-based carriers enhance skeletal stem cell reprogramming towards immunomodulatory phenotype in osteoarthritic therapy. Bioact Mater 2024; 34:204-220. [PMID: 38235309 PMCID: PMC10792171 DOI: 10.1016/j.bioactmat.2023.12.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/13/2023] [Accepted: 12/23/2023] [Indexed: 01/19/2024] Open
Abstract
Skeletal stem cells (SSC) have gained attentions as candidates for the treatment of osteoarthritis due to their osteochondrogenic capacity. However, the immunomodulatory properties of SSC, especially under delivery operations, have been largely ignored. In the study, we found that Pdpn+ and Grem1+ SSC subpopulations owned immunoregulatory potential, and the single-cell RNA sequencing (scRNA-seq) data suggested that the mechanical activation of microgel carriers on SSC induced the generation of Pdpn+Grem1+Ptgs2+ SSC subpopulation, which was potent at suppressing macrophage inflammation. The microgel carriers promoted the YAP nuclear translocation, and the activated YAP protein was necessary for the increased expression of Ptgs2 and PGE2 in microgels-delivered SSC, which further suppressed the expression of TNF-ɑ, IL-1β and promoted the expression of IL-10 in macrophages. SSC delivered with microgels yielded better preventive effects on articular lesions and macrophage activation in osteoarthritic rats than SSC without microgels. Chemically blocking the YAP and Ptgs2 in microgels-delivered SSC partially abolished the enhanced protection on articular tissues and suppression on osteoarthritic macrophages. Moreover, microgel carriers significantly prolonged SSC retention time in vivo without increasing SSC implanting into osteoarthritic joints. Together, our study demonstrated that microgel carriers enhanced SSC reprogramming towards immunomodulatory phenotype to regulate macrophage phenotype transformation for effectively osteoarthritic therapy by promoting YAP protein translocation into nucleus. The study not only complement and perfect the immunological mechanisms of SSC-based therapy at the single-cell level, but also provide new insight for microgel carriers in stem cell-based therapy.
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Affiliation(s)
- Pei-Lin Li
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, PR China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
| | - Da-Fu Chen
- Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Road Xinjiekou 31, Beijing, 100035, PR China
| | - Xiao-Tong Li
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, PR China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
| | - Rui-Cong Hao
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, PR China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
| | - Zhi-Dong Zhao
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, PR China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
- People's Liberation Army General Hospital, Road Fuxing 28, Beijing, 100853, PR China
| | - Zhi-Ling Li
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, PR China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
| | - Bo-Feng Yin
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, PR China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
| | - Jie Tang
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, PR China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
| | - Yu-Wen Luo
- Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Road Xinjiekou 31, Beijing, 100035, PR China
| | - Chu-Tse Wu
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, PR China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
| | - Jing-Jun Nie
- Laboratory of Bone Tissue Engineering, Beijing Laboratory of Biomedical Materials, National Center for Orthopaedics, Beijing Research Institute of Traumatology and Orthopaedics, Beijing Jishuitan Hospital, Capital Medical University, Road Xinjiekou 31, Beijing, 100035, PR China
| | - Heng Zhu
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, PR China
- Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing, 100850, PR China
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Yang F, Xiong WQ, Li CZ, Wu MJ, Zhang XZ, Ran CX, Li ZH, Cui Y, Liu BY, Zhao DW. Extracellular vesicles derived from mesenchymal stem cells mediate extracellular matrix remodeling in osteoarthritis through the transport of microRNA-29a. World J Stem Cells 2024; 16:191-206. [PMID: 38455098 PMCID: PMC10915956 DOI: 10.4252/wjsc.v16.i2.191] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/18/2023] [Accepted: 01/30/2024] [Indexed: 02/26/2024] Open
Abstract
BACKGROUND Knee osteoarthritis (KOA) is a common orthopedic condition with an uncertain etiology, possibly involving genetics and biomechanics. Factors like changes in chondrocyte microenvironment, oxidative stress, inflammation, and immune responses affect KOA development. Early-stage treatment options primarily target symptom relief. Mesenchymal stem cells (MSCs) show promise for treatment, despite challenges. Recent research highlights microRNAs (miRNAs) within MSC-released extracellular vesicles that can potentially promote cartilage regeneration and hinder KOA progression. This suggests exosomes (Exos) as a promising avenue for future treatment. While these findings emphasize the need for effective KOA progression management, further safety and efficacy validation for Exos is essential. AIM To explore miR-29a's role in KOA, we'll create miR-29a-loaded vesicles, testing for early treatment in rat models. METHODS Extraction of bone marrow MSC-derived extracellular vesicles, preparation of engineered vesicles loaded with miR-29a using ultrasonication, and identification using quantitative reverse transcription polymerase chain reaction; after establishing a rat model of KOA, rats were randomly divided into three groups: Blank control group injected with saline, normal extracellular vesicle group injected with normal extracellular vesicle suspension, and engineered extracellular vesicle group injected with engineered extracellular vesicle suspension. The three groups were subjected to general behavioral observation analysis, imaging evaluation, gross histological observation evaluation, histological detection, and immunohistochemical detection to compare and evaluate the progress of various forms of arthritis. RESULTS General behavioral observation results showed that the extracellular vesicle group and engineered extracellular vesicle group had better performance in all four indicators of pain, gait, joint mobility, and swelling compared to the blank control group. Additionally, the engineered extracellular vesicle group had better pain relief at 4 wk and better knee joint mobility at 8 wk compared to the normal extracellular vesicle group. Imaging examination results showed that the blank control group had the fastest progression of arthritis, the normal extracellular vesicle group had a relatively slower progression, and the engineered extracellular vesicle group had the slowest progression. Gross histological observation results showed that the blank control group had the most obvious signs of arthritis, the normal extracellular vesicle group showed signs of arthritis, and the engineered extracellular vesicle group showed no significant signs of arthritis. Using the Pelletier gross score evaluation, the engineered extracellular vesicle group had the slowest progression of arthritis. Results from two types of staining showed that the articular cartilage of rats in the normal extracellular vesicle and engineered extracellular vesicle groups was significantly better than that of the blank control group, and the engineered extracellular vesicle group had the best cartilage cell and joint surface condition. Immunohistochemical detection of type II collagen and proteoglycan showed that the extracellular matrix of cartilage cells in the normal extracellular vesicle and engineered extracellular vesicle groups was better than that of the blank control group. Compared to the normal extracellular vesicle group, the engineered extracellular vesicle group had a better regulatory effect on the extracellular matrix of cartilage cells. CONCLUSION Engineered Exos loaded with miR-29a can exert anti-inflammatory effects and maintain extracellular matrix stability, thereby protecting articular cartilage, and slowing the progression of KOA.
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Affiliation(s)
- Fan Yang
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
| | - Wan-Qi Xiong
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
| | - Chen-Zhi Li
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
| | - Ming-Jian Wu
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
| | - Xiu-Zhi Zhang
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
| | - Chun-Xiao Ran
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
| | - Zhen-Hao Li
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
| | - Yan Cui
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
| | - Bao-Yi Liu
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China.
| | - De-Wei Zhao
- Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
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Campbell TM, Trudel G. Protecting the regenerative environment: selecting the optimal delivery vehicle for cartilage repair-a narrative review. Front Bioeng Biotechnol 2024; 12:1283752. [PMID: 38333081 PMCID: PMC10850577 DOI: 10.3389/fbioe.2024.1283752] [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: 08/27/2023] [Accepted: 01/15/2024] [Indexed: 02/10/2024] Open
Abstract
Focal cartilage defects are common in youth and older adults, cause significant morbidity and constitute a major risk factor for developing osteoarthritis (OA). OA is the most common musculoskeletal (MSK) disease worldwide, resulting in pain, stiffness, loss of function, and is currently irreversible. Research into the optimal regenerative approach and methods in the setting of either focal cartilage defects and/or OA holds to the ideal of resolving both diseases. The two fundamentals required for cartilage regenerative treatment are 1) the biological element contributing to the regeneration (e.g., direct application of stem cells, or of an exogenous secretome), and 2) the vehicle by which the biological element is suspended and delivered. The vehicle provides support to the regenerative process by providing a protective environment, a structure that allows cell adherence and migration, and a source of growth and regenerative factors that can activate and sustain regeneration. Models of cartilage diseases include osteochondral defect (OCD) (which usually involve one focal lesion), or OA (which involves a more diffuse articular cartilage loss). Given the differing nature of these models, the optimal regenerative strategy to treat different cartilage diseases may not be universal. This could potentially impact the translatability of a successful approach in one condition to that of the other. An analogy would be the repair of a pothole (OCD) versus repaving the entire road (OA). In this narrative review, we explore the existing literature evaluating cartilage regeneration approaches for OCD and OA in animal then in human studies and the vehicles used for each of these two conditions. We then highlight strengths and challenges faced by the different approaches presented and discuss what might constitute the optimal cartilage regenerative delivery vehicle for clinical cartilage regeneration.
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Affiliation(s)
- T. Mark Campbell
- Elisabeth Bruyère Hospital, Ottawa, ON, Canada
- Bone and Joint Research Laboratory, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Guy Trudel
- Bone and Joint Research Laboratory, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- The Ottawa Hospital, Department of Medicine, Division of Physical Medicine and Rehabilitation, Ottawa, ON, Canada
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Chen Y, Cheng RJ, Wu Y, Huang D, Li Y, Liu Y. Advances in Stem Cell-Based Therapies in the Treatment of Osteoarthritis. Int J Mol Sci 2023; 25:394. [PMID: 38203565 PMCID: PMC10779279 DOI: 10.3390/ijms25010394] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 12/16/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Osteoarthritis (OA) is a chronic, degenerative joint disease presenting a significant global health threat. While current therapeutic approaches primarily target symptom relief, their efficacy in repairing joint damage remains limited. Recent research has highlighted mesenchymal stem cells (MSCs) as potential contributors to cartilage repair, anti-inflammatory modulation, and immune regulation in OA patients. Notably, MSCs from different sources and their derivatives exhibit variations in their effectiveness in treating OA. Moreover, pretreatment and gene editing techniques of MSCs can enhance their therapeutic outcomes in OA. Additionally, the combination of novel biomaterials with MSCs has shown promise in facilitating the repair of damaged cartilage. This review summarizes recent studies on the role of MSCs in the treatment of OA, delving into their advantages and exploring potential directions for development, with the aim of providing fresh insights for future research in this critical field.
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Affiliation(s)
- Ye Chen
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (R.-J.C.); (Y.W.); (D.H.)
- Rare Diseases Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Chengdu 610041, China
| | - Rui-Juan Cheng
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (R.-J.C.); (Y.W.); (D.H.)
- Rare Diseases Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Chengdu 610041, China
| | - Yinlan Wu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (R.-J.C.); (Y.W.); (D.H.)
- Rare Diseases Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Chengdu 610041, China
| | - Deying Huang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (R.-J.C.); (Y.W.); (D.H.)
- Rare Diseases Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Chengdu 610041, China
| | - Yanhong Li
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (R.-J.C.); (Y.W.); (D.H.)
- Rare Diseases Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Chengdu 610041, China
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.C.); (R.-J.C.); (Y.W.); (D.H.)
- Rare Diseases Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Institute of Immunology and Inflammation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Chengdu 610041, China
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Koo S, Sohn HS, Kim TH, Yang S, Jang SY, Ye S, Choi B, Kim SH, Park KS, Shin HM, Park OK, Kim C, Kang M, Soh M, Yoo J, Kim D, Lee N, Kim BS, Jung Y, Hyeon T. Ceria-vesicle nanohybrid therapeutic for modulation of innate and adaptive immunity in a collagen-induced arthritis model. NATURE NANOTECHNOLOGY 2023; 18:1502-1514. [PMID: 37884660 DOI: 10.1038/s41565-023-01523-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 09/07/2023] [Indexed: 10/28/2023]
Abstract
Commencing with the breakdown of immune tolerance, multiple pathogenic factors, including synovial inflammation and harmful cytokines, are conjointly involved in the progression of rheumatoid arthritis. Intervening to mitigate some of these factors can bring a short-term therapeutic effect, but other unresolved factors will continue to aggravate the disease. Here we developed a ceria nanoparticle-immobilized mesenchymal stem cell nanovesicle hybrid system to address multiple factors in rheumatoid arthritis. Each component of this nanohybrid works individually and also synergistically, resulting in comprehensive treatment. Alleviation of inflammation and modulation of the tissue environment into an immunotolerant-favourable state are combined to recover the immune system by bridging innate and adaptive immunity. The therapy is shown to successfully treat and prevent rheumatoid arthritis by relieving the main symptoms and also by restoring the immune system through the induction of regulatory T cells in a mouse model of collagen-induced arthritis.
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Affiliation(s)
- Sagang Koo
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Republic of Korea
- School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea
| | - Hee Su Sohn
- School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea
| | - Tae Hee Kim
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
- Department of Fusion Research and Collaboration, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Siyeon Yang
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
- Animal Research Laboratory, Institute Pasteur Korea, Seongnam, Republic of Korea
| | - Se Youn Jang
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
- Department of Dentistry, Graduate School, Kyung Hee University, Seoul, Korea
| | - Seongryeol Ye
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
| | - Boomin Choi
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Republic of Korea
| | - Soo Hyeon Kim
- Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea
| | - Kyoung Sun Park
- Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea
| | - Hyun Mu Shin
- Wide River Institute of Immunology, Seoul National University, Hongcheon, Republic of Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ok Kyu Park
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Republic of Korea
| | - Cheesue Kim
- School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea
| | - Mikyung Kang
- Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA
- Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Min Soh
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Republic of Korea
| | - Jin Yoo
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea
| | - Dokyoon Kim
- Department of Bionano Engineering and Bionanotechnology, Hanyang University, Ansan, Republic of Korea
| | - Nohyun Lee
- School of Advanced Materials Engineering, Kookmin University, Seoul, Republic of Korea
| | - Byung-Soo Kim
- School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea.
- Interdisciplinary Program for Bioengineering, Institute of Engineering Research, Seoul National University, Seoul, Republic of Korea.
| | - Youngmee Jung
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea.
- School of Electrical and Electronic Engineering, YU-KIST Institute, Yonsei University, Seoul, Republic of Korea.
| | - Taeghwan Hyeon
- Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul, Republic of Korea.
- School of Chemical and Biological Engineering, and Institute of Chemical Processes, Seoul National University, Seoul, Republic of Korea.
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Xu Y, Wang JY, Meng T, Ma XW, Li H, Li K. Role of hydrogels in osteoarthritis: A comprehensive review. Int J Rheum Dis 2023; 26:2390-2401. [PMID: 37934919 DOI: 10.1111/1756-185x.14968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/23/2023] [Accepted: 10/27/2023] [Indexed: 11/09/2023]
Abstract
Osteoarthritis (OA) is a chronic, degenerative, and age-related disease. It is characterized by chronic inflammation, progressive articular cartilage destruction, and subchondral bone sclerosis. The current effective treatment for OA is limited. Hydrogel is a kind of unique carrier with well-known biocompatibility, softness, and high water content among various biomaterials. Hydrogels are developed for different biomedical applications, for instance, drug delivery, and tissue engineering. To date, a variety of hydrogels-based therapies have been used in OA patients or animal models. In this review, we comprehensively summarized the potential role of hydrogels in chondrocytes proliferation, apoptosis, and inflammatory component production and discussed the impact of hydrogels on OA development. The collection of this information will help better understand the present progress of hydrogels in OA.
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Affiliation(s)
- Yuan Xu
- College of Health Industry, Sichuan Tourism University, Chengdu, China
| | - Jing-Yan Wang
- College of Health Industry, Sichuan Tourism University, Chengdu, China
| | - Tian Meng
- College of Health Industry, Sichuan Tourism University, Chengdu, China
| | - Xue-Wei Ma
- College of Health Industry, Sichuan Tourism University, Chengdu, China
| | - Hao Li
- College of Health Industry, Sichuan Tourism University, Chengdu, China
| | - Kai Li
- College of Health Industry, Sichuan Tourism University, Chengdu, China
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11
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Li ZL, Li XT, Hao RC, Wang FY, Wang YX, Zhao ZD, Li PL, Yin BF, Mao N, Ding L, Zhu H. Human osteoarthritic articular cartilage stem cells suppress osteoclasts and improve subchondral bone remodeling in experimental knee osteoarthritis partially by releasing TNFAIP3. Stem Cell Res Ther 2023; 14:253. [PMID: 37752608 PMCID: PMC10523665 DOI: 10.1186/s13287-023-03411-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 07/07/2023] [Indexed: 09/28/2023] Open
Abstract
BACKGROUND Though articular cartilage stem cell (ACSC)-based therapies have been demonstrated to be a promising option in the treatment of diseased joints, the wide variety of cell isolation, the unknown therapeutic targets, and the incomplete understanding of the interactions of ACSCs with diseased microenvironments have limited the applications of ACSCs. METHODS In this study, the human ACSCs have been isolated from osteoarthritic articular cartilage by advantage of selection of anatomical location, the migratory property of the cells, and the combination of traumatic injury, mechanical stimuli and enzymatic digestion. The protective effects of ACSC infusion into osteoarthritis (OA) rat knees on osteochondral tissues were evaluated using micro-CT and pathological analyses. Moreover, the regulation of ACSCs on osteoarthritic osteoclasts and the underlying mechanisms in vivo and in vitro were explored by RNA-sequencing, pathological analyses and functional gain and loss experiments. The one-way ANOVA was used in multiple group data analysis. RESULTS The ACSCs showed typical stem cell-like characteristics including colony formation and committed osteo-chondrogenic capacity. In addition, intra-articular injection into knee joints yielded significant improvement on the abnormal subchondral bone remodeling of osteoarthritic rats. Bioinformatic and functional analysis showed that ACSCs suppressed osteoarthritic osteoclasts formation, and inflammatory joint microenvironment augmented the inhibitory effects. Further explorations demonstrated that ACSC-derived tumor necrosis factor alpha-induced protein 3 (TNFAIP3) remarkably contributed to the inhibition on osteoarhtritic osteoclasts and the improvement of abnormal subchondral bone remodeling. CONCLUSION In summary, we have reported an easy and reproducible human ACSC isolation strategy and revealed their effects on subchondral bone remodeling in OA rats by releasing TNFAIP3 and suppressing osteoclasts in a diseased microenvironment responsive manner.
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Affiliation(s)
- Zhi-Ling Li
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China
| | - Xiao-Tong Li
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China
| | - Rui-Cong Hao
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China
- Basic Medical College of Anhui Medical University, Hefei, 230032, Anhui Province, People's Republic of China
| | - Fei-Yan Wang
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China
- Basic Medical College of Anhui Medical University, Hefei, 230032, Anhui Province, People's Republic of China
| | - Yu-Xing Wang
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China
- People's Liberation Army General Hospital, Road Fuxing 28, Beijing, 100853, People's Republic of China
| | - Zhi-Dong Zhao
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China
- People's Liberation Army General Hospital, Road Fuxing 28, Beijing, 100853, People's Republic of China
| | - Pei-Lin Li
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China
| | - Bo-Feng Yin
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China
| | - Ning Mao
- Beijing Institute of Basic Medical Sciences, Road Taiping 27, Beijing, 100850, People's Republic of China
| | - Li Ding
- Air Force Medical Center, PLA, Road Fucheng 30, Beijing, 100142, People's Republic of China.
| | - Heng Zhu
- Department of Stem Cells and Regenerative Medicine, Beijing Institute of Radiation Medicine, Road Taiping 27, Beijing, 100850, People's Republic of China.
- Basic Medical College of Anhui Medical University, Hefei, 230032, Anhui Province, People's Republic of China.
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12
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Eremeev A, Pikina A, Ruchko Y, Bogomazova A. Clinical Potential of Cellular Material Sources in the Generation of iPSC-Based Products for the Regeneration of Articular Cartilage. Int J Mol Sci 2023; 24:14408. [PMID: 37833856 PMCID: PMC10572671 DOI: 10.3390/ijms241914408] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 09/06/2023] [Accepted: 09/06/2023] [Indexed: 10/15/2023] Open
Abstract
Inflammatory joint diseases, among which osteoarthritis and rheumatoid arthritis are the most common, are characterized by progressive degeneration of the cartilage tissue, resulting in the threat of limited or lost joint functionality in the absence of treatment. Currently, treating these diseases is difficult, and a number of existing treatment and prevention measures are not entirely effective and are complicated by the patients' conditions, the multifactorial nature of the pathology, and an incomplete understanding of the etiology. Cellular technologies based on induced pluripotent stem cells (iPSCs) can provide a vast cellular resource for the production of artificial cartilage tissue for replacement therapy and allow the possibility of a personalized approach. However, the question remains whether a number of etiological abnormalities associated with joint disease are transmitted from the source cell to iPSCs and their chondrocyte derivatives. Some data state that there is no difference between the iPSCs and their derivatives from healthy and sick donors; however, there are other data indicating a dissimilarity. Therefore, this topic requires a thorough study of the differentiation potential of iPSCs and the factors influencing it, the risk factors associated with joint diseases, and a comparative analysis of the characteristics of cells obtained from patients. Together with cultivation optimization methods, these measures can increase the efficiency of obtaining cell technology products and make their wide practical application possible.
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Affiliation(s)
- Artem Eremeev
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Malaya Pirogovskaya 1a, Moscow 119435, Russia; (A.P.); (A.B.)
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, Moscow 119334, Russia;
| | - Arina Pikina
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Malaya Pirogovskaya 1a, Moscow 119435, Russia; (A.P.); (A.B.)
- Department of Embryology, Faculty of Biology, Lomonosov Moscow State University, GSP-1 Leninskie Gory, Moscow 119991, Russia
| | - Yevgeny Ruchko
- Koltzov Institute of Developmental Biology, Russian Academy of Sciences, 26 Vavilov Street, Moscow 119334, Russia;
| | - Alexandra Bogomazova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, Malaya Pirogovskaya 1a, Moscow 119435, Russia; (A.P.); (A.B.)
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Yin P, Jiang Y, Fang X, Wang D, Li Y, Chen M, Deng H, Tang P, Zhang L. Cell-Based Therapies for Degenerative Musculoskeletal Diseases. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207050. [PMID: 37199688 PMCID: PMC10375105 DOI: 10.1002/advs.202207050] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 04/29/2023] [Indexed: 05/19/2023]
Abstract
Degenerative musculoskeletal diseases (DMDs), including osteoporosis, osteoarthritis, degenerative disc disease, and sarcopenia, present major challenges in the aging population. Patients with DMDs present with pain, functional decline, and reduced exercise tolerance, which result in long-term or permanent deficits in their ability to perform daily activities. Current strategies for dealing with this cluster of diseases focus on relieving pain, but they have a limited capacity to repair function or regenerate tissue. Cell-based therapies have attracted considerable attention in recent years owing to their unique mechanisms of action and remarkable effects on regeneration. In this review, current experimental attempts to use cell-based therapies for DMDs are highlighted, and the modes of action of different cell types and their derivatives, such as exosomes, are generalized. In addition, the latest findings from state-of-the-art clinical trials are reviewed, approaches to improve the efficiency of cell-based therapies are summarized, and unresolved questions and potential future research directions for the translation of cell-based therapies are identified.
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Affiliation(s)
- Pengbin Yin
- Department of Orthopedicsthe Fourth Medical CenterChinese PLA General HospitalBeijing100853China
- National Clinical Research Center for OrthopedicsSports Medicine & RehabilitationBeijing100853China
| | - Yuheng Jiang
- Department of Orthopedicsthe Fourth Medical CenterChinese PLA General HospitalBeijing100853China
- National Clinical Research Center for OrthopedicsSports Medicine & RehabilitationBeijing100853China
- Department of OrthopedicsGeneral Hospital of Southern Theater Command of PLANo. 111, Liuhua AvenueGuangzhou510010China
| | - Xuan Fang
- Department of Anatomy, Histology and EmbryologySchool of Basic Medical SciencesPeking University Health Science CenterBeijing100191China
| | - Daofeng Wang
- Department of Orthopedicsthe Fourth Medical CenterChinese PLA General HospitalBeijing100853China
- National Clinical Research Center for OrthopedicsSports Medicine & RehabilitationBeijing100853China
| | - Yi Li
- Department of Orthopedicsthe Fourth Medical CenterChinese PLA General HospitalBeijing100853China
- National Clinical Research Center for OrthopedicsSports Medicine & RehabilitationBeijing100853China
| | - Ming Chen
- Department of Orthopedicsthe Fourth Medical CenterChinese PLA General HospitalBeijing100853China
- National Clinical Research Center for OrthopedicsSports Medicine & RehabilitationBeijing100853China
| | - Hao Deng
- Department of OrthopedicsThird Affiliated Hospital of Jinzhou Medical UniversityJinzhouLiaoning Province121000China
| | - Peifu Tang
- Department of Orthopedicsthe Fourth Medical CenterChinese PLA General HospitalBeijing100853China
- National Clinical Research Center for OrthopedicsSports Medicine & RehabilitationBeijing100853China
| | - Licheng Zhang
- Department of Orthopedicsthe Fourth Medical CenterChinese PLA General HospitalBeijing100853China
- National Clinical Research Center for OrthopedicsSports Medicine & RehabilitationBeijing100853China
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14
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Kim SJ, Kim JE, Choe G, Song DH, Kim SJ, Kim TH, Yoo J, Kim SH, Jung Y. Self-assembled peptide-substance P hydrogels alleviate inflammation and ameliorate the cartilage regeneration in knee osteoarthritis. Biomater Res 2023; 27:40. [PMID: 37143133 PMCID: PMC10161637 DOI: 10.1186/s40824-023-00387-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 04/26/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Self-assembled peptide (SAP)-substance P (SP) hydrogels can be retained in the joint cavity longer than SP alone, and they can alleviate inflammation and ameliorate cartilage regeneration in knee osteoarthritis (OA). We conducted a preclinical study using diverse animal models of OA and an in vitro study using human synoviocytes and patient-derived synovial fluids to demonstrate the effect of SAP-SP complex on the inflammation and cartilage regeneration. METHODS Surgical induction OA model was prepared with New Zealand white female rabbits and chemical induction, and naturally occurring OA models were prepared using Dunkin Hartely female guinea pigs. The SAP-SP complex or control (SAP, SP, or saline) was injected into the joint cavities in each model. We performed micro-computed tomography (Micro-CT) analysis, histological evaluation, immunofluorescent analysis, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling (TUNEL) assay and analyzed the recruitment of intrinsic mesenchymal stem cells (MSCs), macrophage activity, and inflammatory cytokine in each OA model. Human synoviocytes were cultured in synovial fluid extracted from human OA knee joints injected with SAP-SP complexes or other controls. Proliferative capacity and inflammatory cytokine levels were analyzed. RESULTS Alleviation of inflammation, inhibition of apoptosis, and enhancement of intrinsic MSCs have been established in the SAP-SP group in diverse animal models. Furthermore, the inflammatory effects on human samples were examined in synoviocytes and synovial fluid from patients with OA. In this study, we observed that SAP-SP showed anti-inflammatory action in OA conditions and increased cartilage regeneration by recruiting intrinsic MSCs, inhibiting progression of OA. CONCLUSIONS These therapeutic effects have been validated in diverse OA models, including rabbits, Dunkin Hartley guinea pigs, and human synoviocytes. Therefore, we propose that SAP-SP may be an effective injectable therapeutic agent for treating OA. In this manuscript, we report a preclinical study of novel self-assembled peptide (SAP)-substance P (SP) hydrogels with diverse animal models and human synoviocytes and it displays anti-inflammatory effects, apoptosis inhibition, intrinsic mesenchymal stem cells recruitments and cartilage regeneration.
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Affiliation(s)
- Sang Jun Kim
- Department of Physical and Rehabilitation Medicine, Seoul Jun Rehabilitation Clinic and Research Center, Seoul, Republic of Korea
- Stem Cell & Regenerative Medicine Institute, Samsung Medical Center, Seoul, Republic of Korea
| | - Ji Eun Kim
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
| | - Goeun Choe
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
| | - Da Hyun Song
- Department of Physical and Rehabilitation Medicine, Seoul Jun Rehabilitation Clinic and Research Center, Seoul, Republic of Korea
| | - Sun Jeong Kim
- Stem Cell Institute, ENCell Co. Ltd, Seoul, Republic of Korea
- Cell and Gene Therapy Institute, Samsung Medical Center, Seoul, Republic of Korea
| | - Tae Hee Kim
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
| | - Jin Yoo
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
| | - Soo Hyun Kim
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
| | - Youngmee Jung
- Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea.
- School of Electrical and Electronic Engineering, YU-KIST Institute, Yonsei University, Seoul, Republic of Korea.
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15
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Meng S, Tang C, Deng M, Yuan J, Fan Y, Gao S, Feng Y, Yang J, Chen C. Tropoelastin-Pretreated Exosomes from Adipose-Derived Stem Cells Improve the Synthesis of Cartilage Matrix and Alleviate Osteoarthritis. J Funct Biomater 2023; 14:jfb14040203. [PMID: 37103293 PMCID: PMC10143921 DOI: 10.3390/jfb14040203] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/24/2023] [Accepted: 04/03/2023] [Indexed: 04/28/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have recently been widely used to treat osteoarthritis (OA). Our prior research shows that tropoelastin (TE) increases MSC activity and protects knee cartilage from OA-related degradation. The underlying mechanism might be that TE regulates the paracrine of MSCs. Exosomes (Exos), the paracrine secretion of MSCs, have been found to protect chondrocytes, reduce inflammation, and preserve the cartilage matrix. In this study, we used Exos derived from TE-pretreated adipose-derived stem cells (ADSCs) (TE-ExoADSCs) as an injection medium, and compared it with Exos derived from unpretreated ADSCs (ExoADSCs). We found that TE-ExoADSCs could effectively enhance the matrix synthesis of chondrocytes in vitro. Moreover, TE pretreatment increased the ability of ADSCs to secrete Exos. In addition, compared with ExoADSCs, TE-ExoADSCs exhibited therapeutic effects in the anterior cruciate ligament transection (ACLT)-induced OA model. Further, we observed that TE altered the microRNA expression in ExoADSCs and identified one differentially upregulated microRNA: miR-451-5p. In conclusion, TE-ExoADSCs helped maintain the chondrocyte phenotype in vitro, and promoted cartilage repair in vivo. These therapeutic effects might be related with the altered expression of miR-451-5p in the ExoADSCs. Thus, the intra-articular delivery of Exos derived from ADSCs with TE pretreatment could be a new approach to treat OA.
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Affiliation(s)
- Shuo Meng
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Cong Tang
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Muhai Deng
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Jie Yuan
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Yanli Fan
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Shasha Gao
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
| | - Yong Feng
- Department of Orthopaedic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing 400014, China
| | - Junjun Yang
- Key Laboratory of Biorheological Science and Technology, College of Bioengineering, Chongqing University, Ministry of Education, Chongqing 400044, China
| | - Cheng Chen
- College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China
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Boffa A, Perucca Orfei C, Sourugeon Y, Laver L, Magalon J, Sánchez M, Tischer T, de Girolamo L, Filardo G. Cell-based therapies have disease-modifying effects on osteoarthritis in animal models. A systematic review by the ESSKA Orthobiologic Initiative. Part 2: bone marrow-derived cell-based injectable therapies. Knee Surg Sports Traumatol Arthrosc 2023:10.1007/s00167-023-07320-3. [PMID: 36823238 DOI: 10.1007/s00167-023-07320-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 01/10/2023] [Indexed: 02/25/2023]
Abstract
PURPOSE Aim of this systematic review was to determine if bone marrow-derived cell-based injectable therapies induce disease-modifying effects in joints affected by osteoarthritis (OA) in animal models. METHODS A systematic review was performed on three electronic databases (PubMed, Web of Science, Embase) according to PRISMA guidelines. A synthesis of the results was performed investigating disease-modifying effects in preclinical animal studies comparing injectable bone marrow-derived products with OA controls or other products, different formulations or injection intervals, and the combination with other products. The risk of bias was assessed according to the SYRCLE's tool. RESULTS Fifty-three studies were included (1819 animals) with an increasing publication trend over time. Expanded cells were used in 48 studies, point-of-care products in 3 studies, and both approaches were investigated in 2 studies. Among the 47 studies presenting results on the disease-modifying effects, 40 studies (85%) reported better results with bone marrow-derived products compared to OA controls, with positive findings evident in 14 out of 20 studies (70%) in macroscopic assessment, in 30 out of 41 studies (73%) in histological assessment, and in 10 out of 13 studies (77%) in immunohistochemical evaluations. Clinical evaluations showed positive results in 7 studies out of 9 (78%), positive imaging results in 11 studies out of 17 (65%), and positive biomarker results in 5 studies out of 10 (50%). While 36 out of 46 studies (78%) reported positive results at the cartilage level, only 3 out of 10 studies (30%) could detect positive changes at the synovial level. The risk of bias was low in 42% of items, unclear in 50%, and high in 8%. CONCLUSION This systematic review of preclinical studies demonstrated that intra-articular injections of bone marrow-derived products can induce disease-modifying effects in the treatment of OA, slowing down the progression of cartilage damage with benefits at macroscopic, histological, and immunohistochemical levels. Positive results have been also observed in terms of clinical and imaging findings, as well as in the modulation of inflammatory and cartilage biomarkers, while poor effects have been described on the synovial membrane. These findings are important to understand the potential of bone marrow-derived products and to guide further research to optimise their use in the clinical practice. LEVEL OF EVIDENCE II.
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Affiliation(s)
- Angelo Boffa
- Applied and Translational Research Center, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
- Clinica Ortopedica e Traumatologica 2, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Carlotta Perucca Orfei
- Laboratorio di Biotecnologie Applicate all'Ortopedia, IRCCS Ospedale Galeazzi Sant'Ambrogio, Via Cristina Belgioioso 173, 20157, Milan, Italy.
| | | | - Lior Laver
- Department of Orthopaedics, Hillel Yaffe Medical Center (HYMC), Hadera, Israel
- Arthrosport Clinic, Tel‑Aviv, Israel
- Rappaport Faculty of Medicine, Technion University Hospital (Israel Institute of Technology), Haifa, Israel
| | - Jérémy Magalon
- Cell Therapy Laboratory, Hôpital De La Conception, AP-HM, Marseille, France
- INSERM, NRA, C2VN, Aix Marseille Univ, Marseille, France
- SAS Remedex, Marseille, France
| | - Mikel Sánchez
- Arthroscopic Surgery Unit, Hospital Vithas Vitoria, Vitoria‑Gasteiz, Spain
- Advanced Biological Therapy Unit, Hospital Vithas Vitoria, Vitoria‑Gasteiz, Spain
| | - Thomas Tischer
- Department of Orthopaedic Surgery, University of Rostock, Rostock, Germany
- Department of Orthopaedic and Trauma Surgery, Malteser Waldkrankenhaus St. Marien, Erlangen, Germany
| | - Laura de Girolamo
- Laboratorio di Biotecnologie Applicate all'Ortopedia, IRCCS Ospedale Galeazzi Sant'Ambrogio, Via Cristina Belgioioso 173, 20157, Milan, Italy
| | - Giuseppe Filardo
- Applied and Translational Research Center, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
- Service of Orthopaedics and Traumatology, Department of Surgery, EOC, Lugano, Switzerland
- Faculty of Biomedical Sciences, Università Della Svizzera Italiana, Lugano, Switzerland
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Stem cell-derived small extracellular vesicles containing miR-27b-3p attenuated osteoarthritis through inhibition of leukaemia inhibitory factor. FUNDAMENTAL RESEARCH 2023. [DOI: 10.1016/j.fmre.2023.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023] Open
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Mesenchymal Stromal Cells Laden in Hydrogels for Osteoarthritis Cartilage Regeneration: A Systematic Review from In Vitro Studies to Clinical Applications. Cells 2022; 11:cells11243969. [PMID: 36552733 PMCID: PMC9777087 DOI: 10.3390/cells11243969] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 11/29/2022] [Accepted: 12/05/2022] [Indexed: 12/13/2022] Open
Abstract
This systematic review is focused on the main characteristics of the hydrogels used for embedding the mesenchymal stromal cells (MSCs) in in vitro/ex vivo studies, in vivo OA models and clinical trials for favoring cartilage regeneration in osteoarthritis (OA). PubMED and Embase databases were used to select the papers that were submitted to a public reference manager Rayyan Systematic Review Screening Software. A total of 42 studies were considered eligible: 25 articles concerned in vitro studies, 2 in vitro and ex vivo ones, 5 in vitro and in vivo ones, 8 in vivo ones and 2 clinical trials. Some in vitro studies evidenced a rheological characterization of the hydrogels and description of the crosslinking methods. Only 37.5% of the studies considered at the same time chondrogenic, fibrotic and hypertrophic markers. Ex vivo studies focused on hydrogel adhesion properties and the modification of MSC-laden hydrogels subjected to compression tests. In vivo studies evidenced the effect of cell-laden hydrogels in OA animal models or defined the chondrogenic potentiality of the cells in subcutaneous implantation models. Clinical studies confirmed the positive impact of these treatments on patients with OA. To speed the translation to the clinical use of cell-laden hydrogels, further studies on hydrogel characteristics, injection modalities, chemo-attractant properties and adhesion strength are needed.
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Yu H, Huang Y, Yang L. Research progress in the use of mesenchymal stem cells and their derived exosomes in the treatment of osteoarthritis. Ageing Res Rev 2022; 80:101684. [PMID: 35809775 DOI: 10.1016/j.arr.2022.101684] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/08/2022] [Accepted: 07/05/2022] [Indexed: 12/21/2022]
Abstract
Osteoarthritis (OA), as a common orthopedic disease with cartilage injury as its main pathological feature, has a complex pathogenesis and existing medical technology remains unable to reverse the progress of cartilage degeneration caused thereby. In recent years, mesenchymal stem cells (MSCs) and their secreted exosomes have become a focus of research into cartilage regeneration. MSCs have the potential to differentiate into a variety of cells. Under specific conditions, they can be promoted to differentiate into chondrocytes and maintain the function and stability of chondrocytes. Exosomes secreted by MSCs, as an intercellular messenger, can treat OA in a variety of ways through bioactive factors carried therewith, such as protein, lipid, mRNA, and miRNA. This study reviewed the application of MSCs and their exosomes from different sources in the prevention of OA, which provides a new idea for the treatment of OA.
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Affiliation(s)
- Hongxia Yu
- Departments of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang, China.
| | - Yuling Huang
- Departments of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang, China.
| | - Lina Yang
- Departments of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang, China.
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20
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Dexamethasone-Loaded Radially Mesoporous Silica Nanoparticles for Sustained Anti-Inflammatory Effects in Rheumatoid Arthritis. Pharmaceutics 2022; 14:pharmaceutics14050985. [PMID: 35631571 PMCID: PMC9143902 DOI: 10.3390/pharmaceutics14050985] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/30/2022] [Accepted: 05/01/2022] [Indexed: 02/01/2023] Open
Abstract
Radially mesoporous silica nanoparticles (RMSNs) with protonated amine functionality are proposed to be a dexamethasone (Dex) carrier that could achieve a sustained anti-inflammatory effect in rheumatoid arthritis (RA). High-capacity loading and a sustained release of target drugs were achieved by radially oriented mesopores and surface functionality. The maximum loading efficiency was confirmed to be about 76 wt%, which is about two times greater than that of representative mesopores silica, SBA-15. In addition, Dex-loaded RMSNs allow a sustained-release profile with about 92% of the loaded Dex for 100 h in vitro, resulting in 2.3-fold better delivery efficiency of Dex than that of the SBA-15 over the same period. In vivo evaluation of the inhibitory effects on inflammation in a RA disease rat model showed that, compared with the control groups, the group treated with Dex-loaded RMSNs sustained significant anti-inflammatory effects and recovery of cartilage over a period of 8 weeks. The in vivo effects were confirmed via micro-computed tomography, bone mineral density measurements, and modified Mankin scoring. The proposed Dex-loaded RMSNs prolonged the life of the in vivo concentrations of therapeutic agents and maximized their effect, which should encourage its application.
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21
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Wang G, Xing D, Liu W, Zhu Y, Liu H, Yan L, Fan K, Liu P, Yu B, Li JJ, Wang B. Preclinical studies and clinical trials on mesenchymal stem cell therapy for knee osteoarthritis: A systematic review on models and cell doses. Int J Rheum Dis 2022; 25:532-562. [PMID: 35244339 DOI: 10.1111/1756-185x.14306] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/30/2022] [Accepted: 02/07/2022] [Indexed: 12/15/2022]
Abstract
AIM To provide a systematic analysis of the study design in knee osteoarthritis (OA) preclinical studies, focusing on the characteristics of animal models and cell doses, and to compare these to the characteristics of clinical trials using mesenchymal stem cells (MSCs) for the treatment of knee OA. METHOD A systematic and comprehensive search was conducted using the PubMed, Web of Science, Ovid, and Embase electronic databases for research papers published in 2009-2020 on testing MSC treatment in OA animal models. The PubMed database and ClinicalTrials.gov website were used to search for published studies reporting clinical trials of MSC therapy for knee OA. RESULTS In total, 9234 articles and two additional records were retrieved, of which 120 studies comprising preclinical and clinical studies were included for analysis. Among the preclinical studies, rats were the most commonly used species for modeling knee OA, and anterior cruciate ligament transection was the most commonly used method for inducing OA. There was a correlation between the cell dose and body weight of the animal. In clinical trials, there was large variation in the dose of MSCs used to treat knee OA, ranging from 1 × 106 to 200 × 106 cells with an average of 37.91 × 106 cells. CONCLUSION Mesenchymal stem cells have shown great potential in improving pain relief and tissue protection in both preclinical and clinical studies of knee OA. Further high-quality preclinical and clinical studies are needed to explore the dose effectiveness relationship of MSC therapy and to translate the findings from preclinical studies to humans.
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Affiliation(s)
- Guishan Wang
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, China.,Department of Orthopedic Surgery, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China
| | - Dan Xing
- Arthritis Clinic & Research Center, Peking University People's Hospital, Beijing, China
| | - Wei Liu
- Beijing CytoNiche Biotechnology Co. Ltd, Beijing, China
| | - Yuanyuan Zhu
- Department of Pharmacy, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China
| | - Haifeng Liu
- Department of Orthopedic Surgery, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China
| | - Lei Yan
- Department of Orthopedic Surgery, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China
| | - Kenan Fan
- Department of Health Statistics, School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Peidong Liu
- Department of Orthopedic Surgery, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China
| | - Baofeng Yu
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, China
| | - Jiao Jiao Li
- Faculty of Engineering and IT, School of Biomedical Engineering, University of Technology Sydney, Ultimo, New South Wales, Australia
| | - Bin Wang
- Department of Orthopedic Surgery, Shanxi Medical University Second Affiliated Hospital, Taiyuan, China.,Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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22
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Combinations of Hydrogels and Mesenchymal Stromal Cells (MSCs) for Cartilage Tissue Engineering-A Review of the Literature. Gels 2021; 7:gels7040217. [PMID: 34842678 PMCID: PMC8628761 DOI: 10.3390/gels7040217] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/11/2021] [Accepted: 11/13/2021] [Indexed: 01/17/2023] Open
Abstract
Cartilage offers limited regenerative capacity. Cell-based approaches have emerged as a promising alternative in the treatment of cartilage defects and osteoarthritis. Due to their easy accessibility, abundancy, and chondrogenic potential mesenchymal stromal cells (MSCs) offer an attractive cell source. MSCs are often combined with natural or synthetic hydrogels providing tunable biocompatibility, biodegradability, and enhanced cell functionality. In this review, we focused on the different advantages and disadvantages of various natural, synthetic, and modified hydrogels. We examined the different combinations of MSC-subpopulations and hydrogels used for cartilage engineering in preclinical and clinical studies and reviewed the effects of added growth factors or gene transfer on chondrogenesis in MSC-laden hydrogels. The aim of this review is to add to the understanding of the disadvantages and advantages of various combinations of MSC-subpopulations, growth factors, gene transfers, and hydrogels in cartilage engineering.
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Xing D, Liu W, Wang B, Li JJ, Zhao Y, Li H, Liu A, Du Y, Lin J. Intra-articular Injection of Cell-laden 3D Microcryogels Empower Low-dose Cell Therapy for Osteoarthritis in a Rat Model. Cell Transplant 2021; 29:963689720932142. [PMID: 32608995 PMCID: PMC7563831 DOI: 10.1177/0963689720932142] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Intra-articular injection of mesenchymal stem cells (MSCs) in an osteoarthritic joint can help slow down cartilage destruction. However, cell survival and the efficiency of repair are generally low due to mechanical damage during injection and a high rate of cell loss. We, thus, investigated an improved strategy for cell delivery to an osteoarthritic joint through the use of three-dimensional (3D) microcryogels. MSCs were seeded into 3D microcryogels. The viability and proliferation of MSCs in microcryogels were determined over 5 d, and the phenotype of MSCs was confirmed through trilineage differentiation tests and flow cytometry. In Sprague Dawley rats with induced osteoarthritis (OA) of the knee joint, a single injection was made with the following groups: saline control, low-dose free MSCs (1 × 105 cells), high-dose free MSCs (1 × 106 cells), and microcryogels + MSCs (1 × 105 cells). Cartilage degeneration was evaluated by macroscopic examination, micro-computed tomographic analysis, and histology. MSCs grown in microcryogels exhibited optimal viability and proliferation at 3 d with stable maintenance of phenotype in vitro. Microcryogels seeded with MSCs were, therefore, primed for 3 d before being used for in vivo experiments. At 4 and 8 wk, the microcryogels + MSCs and high-dose free MSC groups had significantly higher International Cartilage Repair Society macroscopic scores, histological evidence of more proteoglycan deposition and less cartilage loss accompanied by a lower Mankin score, and minimal radiographic evidence of osteoarthritic changes in the joint compared to the other two groups. In conclusion, intra-articular injection of cell-laden 3D microcryogels containing a low dose of MSCs can achieve similar effects as a high dose of free MSCs for OA in a rat model. Primed MSCs in 3D microcryogels can be considered as an improved delivery strategy for cell therapy in treating OA that minimizes cell dose while retaining therapeutic efficacy.
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Affiliation(s)
- Dan Xing
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China.,Arthritis Institute, Peking University, Beijing, China.,These authors contributed equally to this article
| | - Wei Liu
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China.,Beijing Cytoniche Biotechnology Co, Ltd., Beijing, China.,These authors contributed equally to this article
| | - Bin Wang
- Department of Orthopaedics, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.,These authors contributed equally to this article
| | - Jiao Jiao Li
- Kolling Institute, University of Sydney, Sydney, NSW, Australia
| | - Yu Zhao
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China.,Arthritis Institute, Peking University, Beijing, China
| | - Hui Li
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China.,Arthritis Institute, Peking University, Beijing, China
| | - Aifeng Liu
- Department of Orthopedics, The First affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China
| | - Jianhao Lin
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China.,Arthritis Institute, Peking University, Beijing, China
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24
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Zhang Q, Xiang E, Rao W, Zhang YQ, Xiao CH, Li CY, Han B, Wu D. Intra-articular injection of human umbilical cord mesenchymal stem cells ameliorates monosodium iodoacetate-induced osteoarthritis in rats by inhibiting cartilage degradation and inflammation. Bone Joint Res 2021; 10:226-236. [PMID: 33739851 PMCID: PMC7998343 DOI: 10.1302/2046-3758.103.bjr-2020-0206.r2] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Aims This study aimed to investigate whether human umbilical cord mesenchymal stem cells (UC-MSCs) can prevent articular cartilage degradation and explore the underlying mechanisms in a rat osteoarthritis (OA) model induced by monosodium iodoacetate (MIA). Methods Human UC-MSCs were characterized by their phenotype and multilineage differentiation potential. Two weeks after MIA induction in rats, human UC-MSCs were intra-articularly injected once a week for three weeks. The therapeutic effect of human UC-MSCs was evaluated by haematoxylin and eosin, toluidine blue, Safranin-O/Fast green staining, and Mankin scores. Markers of joint cartilage injury and pro- and anti-inflammatory markers were detected by immunohistochemistry. Results Histopathological analysis showed that intra-articular injection of human UC-MSCs significantly inhibited the progression of OA, as demonstrated by reduced cartilage degradation, increased Safranin-O staining, and lower Mankin scores. Immunohistochemistry showed that human UC-MSC treatment down-regulated the expression of matrix metalloproteinase-13 (MMP13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), and enhanced the expression of type II collagen and ki67 in the articular cartilage. Furthermore, human UC-MSCs significantly decreased the expression of interleukin (IL)-1β and tumour necrosis factor-α (TNF-α), while increasing TNF-α-induced protein 6 and IL-1 receptor antagonist. Conclusion Our results demonstrated that human UC-MSCs ameliorate MIA-induced OA by preventing cartilage degradation, restoring the proliferation of chondrocytes, and inhibiting the inflammatory response, which implies that human UC-MSCs may be a promising strategy for the treatment of OA. Cite this article: Bone Joint Res 2021;10(3):226–236.
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Affiliation(s)
- Quan Zhang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China.,Wuhan Hamilton Biotechnology Co, Wuhan, China
| | - E Xiang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China.,Wuhan Hamilton Biotechnology Co, Wuhan, China
| | - Wei Rao
- Wuhan Hamilton Biotechnology Co, Wuhan, China
| | - Ya Qi Zhang
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | | | - Chang Yong Li
- Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Bing Han
- Wuhan Hamilton Biotechnology Co, Wuhan, China
| | - Dongcheng Wu
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China.,Wuhan Hamilton Biotechnology Co, Wuhan, China
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25
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Evaluation of Allogeneic Bone-Marrow-Derived and Umbilical Cord Blood-Derived Mesenchymal Stem Cells to Prevent the Development of Osteoarthritis in An Equine Model. Int J Mol Sci 2021; 22:ijms22052499. [PMID: 33801461 PMCID: PMC7958841 DOI: 10.3390/ijms22052499] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/19/2021] [Accepted: 02/24/2021] [Indexed: 12/13/2022] Open
Abstract
Osteoarthritis (OA) is a significant cause of pain in both humans and horses with a high socio-economic impact. The horse is recognized as a pertinent model for human OA. In both species, regenerative therapy with allogeneic mesenchymal stem cells (MSCs) appears to be a promising treatment but, to date, no in vivo studies have attempted to compare the effects of different cell sources on the same individuals. The objective of this study is to evaluate the ability of a single blinded intra-articular injection of allogeneic bone-marrow (BM) derived MSCs and umbilical cord blood (UCB) derived MSC to limit the development of OA-associated pathological changes compared to placebo in a post-traumatic OA model applied to all four fetlock joints of eight horses. The effect of the tissue source (BM vs. UCB) is also assessed on the same individuals. Observations were carried out using clinical, radiographic, ultrasonographic, and magnetic resonance imaging methods as well as biochemical analysis of synovial fluid and postmortem microscopic and macroscopic evaluations of the joints until Week 12. A significant reduction in the progression of OA-associated changes measured with imaging techniques, especially radiography, was observed after injection of bone-marrow derived mesenchymal stem cells (BM-MSCs) compared to contralateral placebo injections. These results indicate that allogeneic BM-MSCs are a promising treatment for OA in horses and reinforce the importance of continuing research to validate these results and find innovative strategies that will optimize the therapeutic potential of these cells. However, they should be considered with caution given the low number of units per group.
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26
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Xing D, Wang K, Wu J, Zhao Y, Liu W, Li JJ, Gao T, Yan D, Wang L, Hao J, Lin J. Clinical-Grade Human Embryonic Stem Cell-Derived Mesenchymal Stromal Cells Ameliorate the Progression of Osteoarthritis in a Rat Model. Molecules 2021; 26:molecules26030604. [PMID: 33498966 PMCID: PMC7865331 DOI: 10.3390/molecules26030604] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 01/13/2021] [Accepted: 01/15/2021] [Indexed: 01/15/2023] Open
Abstract
Mesenchymalstem cell (MSC)-based therapy is being increasingly explored in preclinical and clinical studies as a regenerative method for treating osteoarthritis (OA). However, the use of primary MSCs is hampered by a number of limitations, including donor heterogeneity and inconsistent cell quality. Here, we tested the therapeutic potential of embryonic stem cell-derived MSCs (ES-MSCs) in anOA rat model. ES-MSCs were generated and identified by morphology, trilineage differentiation and flow cytometry. Sprague Dawley rats were treated with either a single dose (106 cells/rat) of ES-MSCs or with three doses spaced one week apart for each dose, starting at four weeks after anterior cruciate ligament transectionto induce OA. Cartilage quality was evaluated at 6 and 10 weeks after treatment with behavioral analysis, macroscopic examination, and histology. At sixweeks after treatment, the groups treated with both single and repeated doses of ES-MSCs had significantly better modified Mankin scores and International Cartilage Repair Society (ICRS) macroscopic scores in the femoral condyle compared to the control group. At 10 weeks after treatment, the repeated doses group had a significantly better ICRS macroscopic scores in the femoral condyle compared to the single dose and control groups. Histological analysis also showed more proteoglycan and less cartilage loss, along with lower Mankin scores in the repeated doses group. In conclusion, treatment with multiple injections of ES-MSCs can ameliorate OA in a rat model. TheES-MSCs have potential to be considered as a regenerative therapy for OA, and can provide an infinite cellular source.
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Affiliation(s)
- Dan Xing
- Arthritis Clinic & Research Center, Peking University People’s Hospital, Peking University, Beijing 100044, China; (D.X.); (K.W.); (Y.Z.)
- Arthritis Institute, Peking University, Beijing 100044, China
| | - Kai Wang
- Arthritis Clinic & Research Center, Peking University People’s Hospital, Peking University, Beijing 100044, China; (D.X.); (K.W.); (Y.Z.)
- Arthritis Institute, Peking University, Beijing 100044, China
| | - Jun Wu
- National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China; (J.W.); (T.G.); (D.Y.); (L.W.)
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Yu Zhao
- Arthritis Clinic & Research Center, Peking University People’s Hospital, Peking University, Beijing 100044, China; (D.X.); (K.W.); (Y.Z.)
- Arthritis Institute, Peking University, Beijing 100044, China
| | - Wei Liu
- Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China;
| | - Jiao Jiao Li
- School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Ultimo, NSW 2007, Australia;
| | - Tingting Gao
- National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China; (J.W.); (T.G.); (D.Y.); (L.W.)
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Deng Yan
- National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China; (J.W.); (T.G.); (D.Y.); (L.W.)
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Liu Wang
- National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China; (J.W.); (T.G.); (D.Y.); (L.W.)
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jie Hao
- National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China; (J.W.); (T.G.); (D.Y.); (L.W.)
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
- Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China
- Correspondence: (J.H.); (J.L.)
| | - Jianhao Lin
- Arthritis Clinic & Research Center, Peking University People’s Hospital, Peking University, Beijing 100044, China; (D.X.); (K.W.); (Y.Z.)
- Arthritis Institute, Peking University, Beijing 100044, China
- Correspondence: (J.H.); (J.L.)
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Deng Z, Jin J, Wang S, Qi F, Chen X, Liu C, Li Y, Ma Y, Lyu F, Zheng Q. Narrative review of the choices of stem cell sources and hydrogels for cartilage tissue engineering. ANNALS OF TRANSLATIONAL MEDICINE 2021; 8:1598. [PMID: 33437797 PMCID: PMC7791208 DOI: 10.21037/atm-20-2342] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Stem cell-based therapy is a promising treatment for cartilage defects due to the pluripotency, abundant sources and low immunogenicity of stem cells. Hydrogels are a promising class of biomaterials for cartilage engineering and are characterized by bioactivity, degradability and elasticity as well as provide water content and mechanical support. The combination of stem cells and hydrogels opens new possibilities for cartilage tissue engineering. However, the selection of suitable types of stem cells and hydrogels is difficult. Currently, various types of stem cells, such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and peripheral blood mononuclear cells (PBMSCs), and various types of hydrogels, including natural polymers, chemically modified natural polymers and synthetic polymers, have been explored based on their potential for cartilage tissue engineering. These materials are used independently or in combination; however, there is no clear understanding of their merits and disadvantages with regard to their suitability for cartilage repair. In this article, we aim to review recent progress in the use of stem cell-hydrogel hybrid constructs for cartilage tissue engineering. We focus on the effects of stem cell types and hydrogel types on efficient chondrogenesis from cellular, preclinical and clinical perspectives. We compare and analyze the advantages and disadvantages of these cells and hydrogels with the hope of increasing discussion of their suitability for cartilage repair and present our perspective on their use for the improvement of physical and biological properties for cartilage tissue engineering.
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Affiliation(s)
- Zhantao Deng
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Jiewen Jin
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shuai Wang
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Fangjie Qi
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xuepan Chen
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Chang Liu
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yanbing Li
- Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yuanchen Ma
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Fengjuan Lyu
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,South China University of Technology-the University of Western Australia Joint Center for Regenerative Medicine Research, School of Medicine, South China University of Technology, Guangzhou, China
| | - Qiujian Zheng
- Department of Orthopedics, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Intra-articular injection of human synovium-derived mesenchymal stem cells in beagles with surgery-induced osteoarthritis. Knee 2021; 28:159-168. [PMID: 33385696 DOI: 10.1016/j.knee.2020.11.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/16/2020] [Accepted: 11/24/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Recently, cell-based tissue engineering approaches using mesenchymal stem cells (MSCs) have been used to treat osteoarthritis (OA). However, the efficacy of human synovium-derived MSCs (hSD-MSCs) has not yet been tested in a canine model of OA. The purpose of this study was to investigate the therapeutic effects of intra-articular hSD-MSC injections in a canine OA model. METHODS Sixty beagles underwent surgical manipulation to induce OA and received intra-articular injection 4 weeks after surgery. The dogs were divided into five groups (n = 12) according to the injection material: G1, sham group; G2, control group injected with phosphate-buffered saline; G3, G4, and G5, experimental groups injected with different hSD-MSC dosages (G3, 2.4 × 106 cells; G4, 4.8 × 106 cells; G5, 9.6 × 106 cells). Magnetic resonance imaging (MRI) and histopathological and immunohistochemical examinations were performed 6 and 24 weeks after injection. RESULTS MRI revealed significant improvements in synovitis 24 weeks after injection in the hSD-MSC-injected groups (G3-G5). Histopathologic analyses showed that cartilage structure and proteoglycan staining were also significantly improved in these groups (G3-G5) 6 weeks after injection and improved further after 24 weeks. Immunohistochemical analysis revealed significant differences in the levels of collagen types I and II between the hSD-injected groups (G3-G5), indicating a similar extracellular matrix (ECM) composition to naïve articular cartilage. CONCLUSION Our study demonstrated for the first time that intra-articular hSD-MSC injection ameliorates the progression of canine OA by restoring cartilage, promoting ECM synthesis, and inhibiting the inflammatory response.
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29
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Mesenchymal Stem Cell Therapy for Osteoarthritis: Practice and Possible Promises. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1387:107-125. [DOI: 10.1007/5584_2021_695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Kangari P, Talaei-Khozani T, Razeghian-Jahromi I, Razmkhah M. Mesenchymal stem cells: amazing remedies for bone and cartilage defects. Stem Cell Res Ther 2020; 11:492. [PMID: 33225992 PMCID: PMC7681994 DOI: 10.1186/s13287-020-02001-1] [Citation(s) in RCA: 156] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022] Open
Abstract
Skeletal disorders are among the leading debilitating factors affecting millions of people worldwide. The use of stem cells for tissue repair has raised many promises in various medical fields, including skeletal disorders. Mesenchymal stem cells (MSCs) are multipotent stromal cells with mesodermal and neural crest origin. These cells are one of the most attractive candidates in regenerative medicine, and their use could be helpful in repairing and regeneration of skeletal disorders through several mechanisms including homing, angiogenesis, differentiation, and response to inflammatory condition. The most widely studied sources of MSCs are bone marrow (BM), adipose tissue, muscle, umbilical cord (UC), umbilical cord blood (UCB), placenta (PL), Wharton's jelly (WJ), and amniotic fluid. These cells are capable of differentiating into osteoblasts, chondrocytes, adipocytes, and myocytes in vitro. MSCs obtained from various sources have diverse capabilities of secreting many different cytokines, growth factors, and chemokines. It is believed that the salutary effects of MSCs from different sources are not alike in terms of repairing or reformation of injured skeletal tissues. Accordingly, differential identification of MSCs' secretome enables us to make optimal choices in skeletal disorders considering various sources. This review discusses and compares the therapeutic abilities of MSCs from different sources for bone and cartilage diseases.
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Affiliation(s)
- Parisa Kangari
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Tissue Engineering Laboratory, Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mahboobeh Razmkhah
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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31
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Ryu JS, Jeong EJ, Kim JY, Park SJ, Ju WS, Kim CH, Kim JS, Choo YK. Application of Mesenchymal Stem Cells in Inflammatory and Fibrotic Diseases. Int J Mol Sci 2020; 21:ijms21218366. [PMID: 33171878 PMCID: PMC7664655 DOI: 10.3390/ijms21218366] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 10/29/2020] [Accepted: 11/05/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various tissues in the adult body. MSCs should be characterized by three criteria for regenerative medicine. MSCs must (1) adhere to plastic surfaces, (2) express specific surface antigens, and (3) differentiate into mesodermal lineages, including chondrocytes, osteoblasts, and adipocytes, in vitro. Interestingly, MSCs have immunomodulatory features and secrete trophic factors and immune receptors that regulate the microenvironment in host tissue. These specific and unique therapeutic properties make MSCs ideal as therapeutic agents in vivo. Specifically, pre-clinical and clinical investigators generated inflammatory and fibrotic diseases models, and then transplantation of MSCs into diseases models for therapeutic effects investigation. In this review, we characterize MSCs from various tissues and describe their applications for treating various inflammation and fibrotic diseases.
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Affiliation(s)
- Jae-Sung Ryu
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Konyang University, Daejeon 35365, Korea; (J.-S.R.); (J.-Y.K.)
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Eun-Jeong Jeong
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea;
| | - Jong-Yeup Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Konyang University, Daejeon 35365, Korea; (J.-S.R.); (J.-Y.K.)
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Soon Ju Park
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
| | - Won Seok Ju
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
| | - Chang-Hyun Kim
- College of Medicine, Dongguk University, Goyang 10326, Korea;
| | - Jang-Seong Kim
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea;
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea
| | - Young-Kug Choo
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
- Correspondence:
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Özdemir E, Emet A, Hashemihesar R, Yürüker ACS, Kılıç E, Uçkan Çetinkaya D, Turhan E. Articular Cartilage Regeneration Utilizing Decellularized Human Placental Scaffold, Mesenchymal Stem Cells and Platelet Rich Plasma. Tissue Eng Regen Med 2020; 17:901-908. [PMID: 33030679 DOI: 10.1007/s13770-020-00298-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 08/10/2020] [Accepted: 08/26/2020] [Indexed: 10/23/2022] Open
Abstract
BACKGROUND Articular cartilage repair has been a challenge in orthopedic practice due to the limited self-regenerative capability. Optimal treatment method for cartilage defects has not been defined. We investigated the effect of decellularized human placental (DHP) scaffold, mesenchymal stem cells (MSC) and platelet-rich plasma (PRP) on hyaline cartilage regeneration in a rat model. METHODS An osteochondral defect was created in trochlea region of the femur in all groups, bilaterally. No additional procedure was performed in control group (n = 14). Only the DHP scaffold was applied to the P group (n = 14). The DHP scaffold and 1 × 106 MSCs were applied to the PS group (n = 14). The DHP scaffold and PRP were applied to the PP group (n = 14). The DHP scaffold, 1 × 106 MSCs and PRP were applied to the PSP group (n = 14). Outcome measures at 12 weeks included Pineda histology score and qualitative histology. RESULTS The mean Pineda scores of P, PS, PP, and PSP groups were significantly better than the control group (p = 0.031, p = 0.002, p < 0.001, p < 0001, respectively). There was no statistically difference in mean Pineda scores of P, PS, PP, and PSP groups (p > 0.05). CONCLUSION In conclusion, the DHP scaffold appears to be a promising scaffold on hyaline cartilage regeneration. The augmentation of DHP scaffold with MSCs and PRP combinations did not enhance its efficacy on articular cartilage regeneration.
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Affiliation(s)
- Erdi Özdemir
- Department of Orthopedics and Traumatology, Faculty of Medicine, Hacettepe University, 06230, Ankara, Turkey.
| | - Abdülsamet Emet
- Department of Orthopedics and Traumatology, Faculty of Medicine, Hacettepe University, 06230, Ankara, Turkey
| | - Ramin Hashemihesar
- Department of Histology and Embryology, Faculty of Medicine, Istanbul Aydin University, 34295, Istanbul, Turkey
| | | | - Emine Kılıç
- Center for Stem Cell Research and Development, Hacettepe University, 06100, Ankara, Turkey
| | - Duygu Uçkan Çetinkaya
- Center for Stem Cell Research and Development, Hacettepe University, 06100, Ankara, Turkey
| | - Egemen Turhan
- Department of Orthopedics and Traumatology, Faculty of Medicine, Hacettepe University, 06230, Ankara, Turkey
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Huňáková K, Hluchý M, Špaková T, Matejová J, Mudroňová D, Kuricová M, Rosocha J, Ledecký V. Study of bilateral elbow joint osteoarthritis treatment using conditioned medium from allogeneic adipose tissue-derived MSCs in Labrador retrievers. Res Vet Sci 2020; 132:513-520. [PMID: 32805699 DOI: 10.1016/j.rvsc.2020.08.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 08/03/2020] [Accepted: 08/05/2020] [Indexed: 02/08/2023]
Abstract
Canine elbow dysplasia is a common cause of forelimb lameness in dogs and can lead to development of osteoarthritis (OA). A potential alternative to pain management is the use of a safe cell-free based therapy through trophic and paracrine factors of mesenchymal stem cells (MSCs). The aim of study was to identify the profile of selected mediators of potential clinical relevance in synovial fluid (SF) samples of dogs with elbow OA and analyse the range of motion (ROM) before and after cell-free MSCs-based treatment. In this study, conditioned medium from allogeneic canine adipose tissue - derived MSC (CM-AD-MSC) was prepared and administered into both elbow joints with OA in six Labrador retriever dogs (n = 6) on day 0 and 14 without creating a control group with a placebo. The SF of the elbow joints was analysed for the presence of several biomolecules (IL-6, IL-10, IL-8, IL-2, IL-12, TNF-αIFN-γ, MMP-3TIMP-1) before and after intraarticular applications of CM-AD-MSC. Kinematic analysis was used to assess the clinical effect of CM-AD-MSC. Analyses of SF and ROM were performed on days 0, 14 and 42. Concentration levels of MMP-3, TIMP-1, IL-6 and TNF-α in SF showed significant differences before and after the treatment (P < .05). There was a significant improvement in ROM between day 0 and 42 (P < .001). No severe adverse events were observed during the study. Results support the potential supportive effect of CM-AD-MSC as a noninvasive therapeutic tool for pain management of OA elbow joints in dogs.
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Affiliation(s)
- Kristína Huňáková
- Small Animal Clinic, University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia
| | - Marián Hluchý
- Small Animal Clinic, University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia
| | - Tímea Špaková
- Associated Tissue Bank, Faculty of Medicine, P. J. Safarik University and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Košice, Slovakia.
| | - Jana Matejová
- Associated Tissue Bank, Faculty of Medicine, P. J. Safarik University and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Košice, Slovakia
| | - Dagmar Mudroňová
- Institute of Immunology, University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia
| | - Mária Kuricová
- Small Animal Clinic, University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia
| | - Ján Rosocha
- Associated Tissue Bank, Faculty of Medicine, P. J. Safarik University and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Košice, Slovakia
| | - Valent Ledecký
- Small Animal Clinic, University of Veterinary Medicine and Pharmacy, Komenského 73, 041 81 Košice, Slovakia
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Clinical Application Status of Articular Cartilage Regeneration Techniques: Tissue-Engineered Cartilage Brings New Hope. Stem Cells Int 2020; 2020:5690252. [PMID: 32676118 PMCID: PMC7345961 DOI: 10.1155/2020/5690252] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Revised: 05/22/2020] [Accepted: 05/28/2020] [Indexed: 12/16/2022] Open
Abstract
Hyaline articular cartilage lacks blood vessels, lymphatics, and nerves and is characterised by limited self-repair ability following injury. Traditional techniques of articular cartilage repair and regeneration all have certain limitations. The development of tissue engineering technology has brought hope to the regeneration of articular cartilage. The strategies of tissue-engineered articular cartilage can be divided into three types: “cell-scaffold construct,” cell-free, and scaffold-free. In “cell-scaffold construct” strategies, seed cells can be autologous chondrocytes or stem. Among them, some commercial products with autologous chondrocytes as seed cells, such as BioSeed®-C and CaReS®, have been put on the market and some products are undergoing clinical trials, such as NOVOCART® 3D. The stem cells are mainly pluripotent stem cells and mesenchymal stem cells from different sources. Cell-free strategies that indirectly utilize the repair and regeneration potential of stem cells have also been used in clinical settings, such as TruFit and MaioRegen. Finally, the scaffold-free strategy is also a new development direction, and the short-term repair results of related products, such as NOVOCART® 3D, are encouraging. In this paper, the commonly used techniques of articular cartilage regeneration in surgery are reviewed. By studying different strategies and different seed cells, the clinical application status of tissue-engineered articular cartilage is described in detail.
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Xing D, Wu J, Wang B, Liu W, Liu W, Zhao Y, Wang L, Li JJ, Liu A, Zhou Q, Hao J, Lin J. Intra-articular delivery of umbilical cord-derived mesenchymal stem cells temporarily retard the progression of osteoarthritis in a rat model. Int J Rheum Dis 2020; 23:778-787. [PMID: 32319197 DOI: 10.1111/1756-185x.13834] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 02/27/2020] [Accepted: 03/05/2020] [Indexed: 12/21/2022]
Abstract
AIM Mesenchymal stem cell (MSC)-based therapy is being explored in treating osteoarthritis (OA). Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) are least reported. In this study, we investigated the effects of single intra-articular injections of hUC-MSCs on a rat OA model. METHOD hUC-MSCs were isolated from the Wharton's jelly of the human umbilical cord and identified. Eighteen Sprague-Dawley rats were used for the OA model. All rats were divided into 3 groups: hyaluronic acid (HA)+MSCs (n = 6), HA (n = 6), and control group (n = 6). One by 106 hUC-MSCs in 100 μL HA, 100 μL HA or 100 μL saline were injected into the knee joint 4 weeks post-surgery as a single dose. Cartilage degeneration was evaluated at 6 and 12 weeks after treatment with macroscopic examination, micro-computed tomography analysis, behavioral analysis, and histology. RESULTS At 6 weeks, the HA + MSCs group had a significantly better International Cartilage Repair Society score in the femoral condyle compared to the HA and control groups. Histological analysis also showed more proteoglycan and less cartilage loss, with lower modified Mankin score in the HA + MSCs group. However, at 12 weeks there were no significant differences between groups from macroscopic examination and histological analysis. Subchondral bone sclerosis of the medial femoral condyle and behavioral tests showed no significant differences between groups at 6 and 12 weeks. CONCLUSION These findings indicate that single injection of hUC-MSCs can have temporary effects on decelerating the progression of cartilage degeneration in OA rats, but may not inhibit OA progression in the long-term.
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Affiliation(s)
- Dan Xing
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China.,Arthritis Institute, Peking University, Beijing, China
| | - Jun Wu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Stem Cell Bank, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Bin Wang
- Department of Sports Medicine and Adult Reconstruction Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Wei Liu
- Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, China.,Beijing CytoNiche Biotechnology Co. Ltd., Beijing, China
| | - Wenjing Liu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Stem Cell Bank, Chinese Academy of Sciences, Beijing, China
| | - Yu Zhao
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China.,Arthritis Institute, Peking University, Beijing, China
| | - Liu Wang
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Stem Cell Bank, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Jiao Jiao Li
- Kolling Institute, University of Sydney, Sydney, NSW, Australia
| | - Aifeng Liu
- Department of Orthopedics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qi Zhou
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Stem Cell Bank, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China.,Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
| | - Jie Hao
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.,Beijing Stem Cell Bank, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jianhao Lin
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China.,Arthritis Institute, Peking University, Beijing, China
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Wang AT, Zhang QF, Wang NX, Yu CY, Liu RM, Luo Y, Zhao YJ, Xiao JH. Cocktail of Hyaluronic Acid and Human Amniotic Mesenchymal Cells Effectively Repairs Cartilage Injuries in Sodium Iodoacetate-Induced Osteoarthritis Rats. Front Bioeng Biotechnol 2020; 8:87. [PMID: 32211385 PMCID: PMC7068044 DOI: 10.3389/fbioe.2020.00087] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 01/30/2020] [Indexed: 12/17/2022] Open
Abstract
Osteoarthritis (OA) is one of the most common refractory degenerative articular cartilage diseases. Human amniotic mesenchymal cells (hAMSCs) have emerged as a promising stem cell source for cartilage repair, and hyaluronic acid (HA) has proven to be a versatile regulator for stem cell transplantation. Herein, an effective and straightforward intra-articular injection therapy using a cocktail of hAMSCs and HA was developed to treat knee OA in a rat model. The injured cartilage was remarkably regenerated, yielding results comparable to normal cartilage levels after 56 days of treatment. Both hAMSCs and HA were indispensable organic components in this therapy, in which HA could synergistically enhance the effects of hAMSCs on cartilage repair. The regenerative mechanism was attributed to the fact that the addition of HA comprehensively enhances the activities of hAMSCs, including chondrogenic differentiation, proliferation, colonization, and regenerative modulation. This cocktail paves a new avenue for injection therapy to treat OA, holding the potential to realize rapid clinical translation.
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Affiliation(s)
- Ai-Tong Wang
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Qing-Fang Zhang
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Nuo-Xin Wang
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Chang-Yin Yu
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ru-Ming Liu
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yi Luo
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yu-Jie Zhao
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jian-Hui Xiao
- Zunyi Municipal Key Laboratory of Medicinal Biotechnology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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Zhang R, Ma J, Han J, Zhang W, Ma J. Mesenchymal stem cell related therapies for cartilage lesions and osteoarthritis. Am J Transl Res 2019; 11:6275-6289. [PMID: 31737182 PMCID: PMC6834499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 08/09/2019] [Indexed: 06/10/2023]
Abstract
Osteoarthritis (OA) is a common degenerative joint disease characterized by cartilage degradation, synovitis, subchondral bone sclerosis and osteophyte formation. Current therapeutic approaches for OA are not curative and only temporarily alleviate symptoms. In recent years, pre-clinical experiments and clinical trials have demonstrated that mesenchymal stem cell (MSC) related therapy is a promising option for the treatment of cartilage lesions and OA. MSCs isolated from bone marrow (BMSCs) have been widely used in animal models and clinic practice to demonstrate their chondrogenic potential, however the incidence of BMSC donors is low. Adipose derived mesenchymal stem cells (AMSCs) are a more easily accessible source of stem cells for OA treatment. MSC related therapies for cartilage lesions and OA include tissue engineering of MSC transplantation, scaffold-free injection of stem cells and cell-free injection of exosomes into the injured joints. Although a great deal of effort is required at the basic and clinical research fronts, the promise is that improved cell-based therapies will ultimately lead to the repair of damaged or diseased joints, and MSC exosome therapy for OA could be a safer, cheaper and a more effective treatment modality. MSC related therapy is predicted to become a regular and routine regenerative medicine for OA treatment in future clinical practice.
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Affiliation(s)
- Rui Zhang
- Translational Medicine Center, Honghui Hospital, Xi’an Jiaotong UniversityXi’an 710054, Shaanxi, China
| | - Jie Ma
- School of Basic Medicine, Xi’an Jiaotong University Health Science CenterXi’an 710061, Shaanxi, China
| | - Jing Han
- School of Basic Medicine, Xi’an Jiaotong University Health Science CenterXi’an 710061, Shaanxi, China
| | - Weijie Zhang
- Department of Joint Surgery, Honghui Hospital, Xi’an Jiaotong UniversityXi’an 710054, Shaanxi, China
| | - Jianbing Ma
- Department of Joint Surgery, Honghui Hospital, Xi’an Jiaotong UniversityXi’an 710054, Shaanxi, China
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Sakamoto T, Miyazaki T, Watanabe S, Takahashi A, Honjoh K, Nakajima H, Oki H, Kokubo Y, Matsumine A. Intraarticular injection of processed lipoaspirate cells has anti-inflammatory and analgesic effects but does not improve degenerative changes in murine monoiodoacetate-induced osteoarthritis. BMC Musculoskelet Disord 2019; 20:335. [PMID: 31324245 PMCID: PMC6642531 DOI: 10.1186/s12891-019-2710-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 07/09/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Previous basic research and clinical studies examined the effects of mesenchymal stem cells (MSCs) on regeneration and maintenance of articular cartilage. However, our pilot study suggested that MSCs are more effective at suppressing inflammation and pain rather than promoting cartilage regeneration in osteoarthritis. Adipose tissue is considered a useful source of MSCs; it can be harvested easily in larger quantities compared with the bone marrow. The present study was designed to evaluate the anti-inflammatory, analgesic, and regenerative effects of intra-articularly injected processed lipoaspirate (PLA) cells (containing adipose-derived MSCs) on degenerative cartilage in a rat osteoarthritis model. METHODS PLA cells were isolated from subcutaneous adipose tissue of 12-week-old female Sprague-Dawley rats. Osteoarthritis was induced by injection of monoiodoacetate (MIA). Each rat received 1 × 106 MSCs into the joint at day 7 (early injection group) and day 14 (late injection group) post-MIA injection. At 7, 14, 21 days after MIA administration, pain was assessed by immunostaining and western blotting of dorsal root ganglion (DRG). Cartilage quality was assessed macroscopically and by safranin-O and H&E staining, and joint inflammation was assessed by western blotting of the synovium. RESULTS The early injection group showed less cartilage degradation, whereas the late injection group showed cartilage damage similar to untreated OA group. The relative expression level of CGRP protein in DRG neurons was significantly lower in the two treatment groups, compared with the untreated group. CONCLUSIONS Intra-articular injection of PLA cells prevented degenerative changes in the early injection group, but had little effect in promoting cartilage repair in the late injection group. Interestingly, intra-articular injection of PLA cells resulted in suppression of inflammation and pain in both OA groups. Further studies are needed to determine the long-term effects of intra-articular injection of PLA cells in osteoarthritis.
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Affiliation(s)
- Takumi Sakamoto
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki 23-3, Eiheiji, Fukui, 910-1193, Japan
| | - Tsuyoshi Miyazaki
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki 23-3, Eiheiji, Fukui, 910-1193, Japan.
| | - Shuji Watanabe
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki 23-3, Eiheiji, Fukui, 910-1193, Japan
| | - Ai Takahashi
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki 23-3, Eiheiji, Fukui, 910-1193, Japan
| | - Kazuya Honjoh
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki 23-3, Eiheiji, Fukui, 910-1193, Japan
| | - Hideaki Nakajima
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki 23-3, Eiheiji, Fukui, 910-1193, Japan
| | - Hisashi Oki
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki 23-3, Eiheiji, Fukui, 910-1193, Japan
| | - Yasuo Kokubo
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki 23-3, Eiheiji, Fukui, 910-1193, Japan
| | - Akihiko Matsumine
- Department of Orthopaedics and Rehabilitation Medicine, Faculty of Medical Sciences, University of Fukui, Matsuoka Shimoaizuki 23-3, Eiheiji, Fukui, 910-1193, Japan
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McKinney JM, Doan TN, Wang L, Deppen J, Reece DS, Pucha KA, Ginn S, Levit RD, Willett NJ. Therapeutic efficacy of intra-articular delivery of encapsulated human mesenchymal stem cells on early stage osteoarthritis. Eur Cell Mater 2019; 37:42-59. [PMID: 30693466 PMCID: PMC7549187 DOI: 10.22203/ecm.v037a04] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Mesenchymal stem cells (MSCs) represent a great therapeutic promise in pre-clinical models of osteoarthritis (OA), but many questions remain as to their therapeutic mechanism of action: engraftment versus paracrine action. Encapsulation of human MSCs (hMSCs) in sodium alginate microspheres allowed for the paracrine signaling properties of these cells to be isolated and studied independently of direct cellular engraftment. The objective of the present study was to quantitatively assess the efficacy of encapsulated hMSCs as a disease-modifying therapeutic for OA, using a medial meniscal tear (MMT) rat model. It was hypothesized that encapsulated hMSCs would have a therapeutic effect, through paracrine-mediated action, on early OA development. Lewis rats underwent MMT surgery to induce OA. 1 d post-surgery, rats received intra-articular injections of encapsulated hMSCs or controls (i.e., saline, empty capsules, non-encapsulated hMSCs). Microstructural changes in the knee joint were quantified using equilibrium partitioning of a ionic contrast agent based micro-computed tomography (EPIC-μCT) at 3 weeks post-surgery, an established time point for early OA. Encapsulated hMSCs significantly attenuated MMT-induced increases in articular cartilage swelling and surface roughness and augmented cartilaginous and mineralized osteophyte volumes. Cellular encapsulation allowed to isolate the hMSC paracrine signaling effects and demonstrated that hMSCs could exert a chondroprotective therapeutic role on early stage OA through paracrine signaling alone. In addition to this chondroprotective role, encapsulated hMSCs augmented the compensatory increases in osteophyte formation. The latter should be taken into strong consideration as many clinical trials using MSCs for OA are currently ongoing.
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Affiliation(s)
| | | | | | | | | | | | | | | | - N J Willett
- Atlanta Veteran Affairs Medical Center, 1670 Clairmont Rd, Room 5A-115, Decatur, GA 30033,
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Mesenchymal stem cell-based therapy of osteoarthritis: Current knowledge and future perspectives. Biomed Pharmacother 2018; 109:2318-2326. [PMID: 30551490 DOI: 10.1016/j.biopha.2018.11.099] [Citation(s) in RCA: 197] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 10/30/2018] [Accepted: 11/25/2018] [Indexed: 02/07/2023] Open
Abstract
Osteoarthritis (OA) is a chronic, prevalent, debilitating joint disease characterized by progressive cartilage degradation, subchondral bone remodeling, bone marrow lesions, meniscal damage, and synovitis. Innate immune cells (natural killer cells, macrophages, and mast cells) play the most important pathogenic role in the early inflammatory response, while cells of adaptive immunity (CD4 + Th1 lymphocytes and antibody producing B cells) significantly contribute to the development of chronic, relapsing course of inflammation in OA patients. Conventional therapy for OA is directed toward symptomatic treatment, mainly pain management, and is not able to promote regeneration of degenerated cartilage or to attenuate joint inflammation. Since articular cartilage, intra-articular ligaments, and menisci have no ability to heal, regeneration of these tissues remains one of the most important goals of new therapeutic approaches used for OA treatment. Due to their capacity for differentiation into chondrocytes and due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have been the most extensively explored as new therapeutic agents in the cell-based therapy of OA. Simple acquisition, rapid proliferation, maintenance of differentiation potential after repeated passages in vitro, minor immunological rejection due to the low surface expression of major histocompatibility complex antigens, efficient engraftment and long-term coexistence in the host are the main characteristics of MSCs that enable their therapeutic use in OA. In this review article, we emphasized current knowledge and future perspectives regarding molecular and cellular mechanisms responsible for beneficial effects of autologous and allogeneic MSCs in the treatment of OA.
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Injectable Systems for Intra-Articular Delivery of Mesenchymal Stromal Cells for Cartilage Treatment: A Systematic Review of Preclinical and Clinical Evidence. Int J Mol Sci 2018. [PMID: 30366400 DOI: 10.3390/ijms19113322.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Stem cell-based therapy is a promising approach to treat cartilage lesions and clinical benefits have been reported in a number of studies. However, the efficacy of cell injection procedures may be impaired by cell manipulation and damage as well as by cell dissemination to non-target tissues. To overcome such issues, mesenchymal stromal cell (MSC) delivery may be performed using injectable vehicles as containment systems that further provide a favorable cell microenvironment. The aim of this systematic review was to analyze the preclinical and clinical literature on platelet-rich plasma (PRP), hyaluronic acid (HA), and hydrogels for the delivery of MSCs. The systematic literature search was performed using the PubMed and Web of science databases with the following string: "(stem cells injection) AND (platelet rich plasma OR PRP OR platelet concentrate OR biomaterials OR hyaluronic acid OR hydrogels)": 40 studies (19 preclinical and 21 clinical) met the inclusion criteria. This review revealed an increasing interest on the use of injectable agents for MSC delivery. However, while negligible adverse events and promising clinical outcomes were generally reported, the prevalence of low quality studies hinders the possibility to demonstrate the real benefits of using such injectable systems. Specific studies must be designed to clearly demonstrate the added benefits of these systems to deliver MSCs for the treatment of cartilage lesions and osteoarthritis.
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Roffi A, Nakamura N, Sanchez M, Cucchiarini M, Filardo G. Injectable Systems for Intra-Articular Delivery of Mesenchymal Stromal Cells for Cartilage Treatment: A Systematic Review of Preclinical and Clinical Evidence. Int J Mol Sci 2018; 19:ijms19113322. [PMID: 30366400 PMCID: PMC6274908 DOI: 10.3390/ijms19113322] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/19/2018] [Accepted: 10/20/2018] [Indexed: 12/16/2022] Open
Abstract
Stem cell-based therapy is a promising approach to treat cartilage lesions and clinical benefits have been reported in a number of studies. However, the efficacy of cell injection procedures may be impaired by cell manipulation and damage as well as by cell dissemination to non-target tissues. To overcome such issues, mesenchymal stromal cell (MSC) delivery may be performed using injectable vehicles as containment systems that further provide a favorable cell microenvironment. The aim of this systematic review was to analyze the preclinical and clinical literature on platelet-rich plasma (PRP), hyaluronic acid (HA), and hydrogels for the delivery of MSCs. The systematic literature search was performed using the PubMed and Web of science databases with the following string: "(stem cells injection) AND (platelet rich plasma OR PRP OR platelet concentrate OR biomaterials OR hyaluronic acid OR hydrogels)": 40 studies (19 preclinical and 21 clinical) met the inclusion criteria. This review revealed an increasing interest on the use of injectable agents for MSC delivery. However, while negligible adverse events and promising clinical outcomes were generally reported, the prevalence of low quality studies hinders the possibility to demonstrate the real benefits of using such injectable systems. Specific studies must be designed to clearly demonstrate the added benefits of these systems to deliver MSCs for the treatment of cartilage lesions and osteoarthritis.
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Affiliation(s)
- Alice Roffi
- Laboratory of Nano-Biotechnology-IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
| | - Norimasa Nakamura
- Institute for Medical Science in Sports, Osaka Health Science University, Osaka 590-0496, Japan.
| | - Mikel Sanchez
- Arthroscopic Surgery Unit-UCA, Hospital Vithas San Jose, 01008 Vitoria-Gasteiz, Spain.
| | - Magali Cucchiarini
- Center of Experimental Orthopaedics, Saarland University Medical Center, 66421 Homburg/Saar, Germany.
| | - Giuseppe Filardo
- Applied and Translational Research (ATR) Center-IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy.
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Comparative efficacy of stem cells and secretome in articular cartilage regeneration: a systematic review and meta-analysis. Cell Tissue Res 2018; 375:329-344. [PMID: 30084022 DOI: 10.1007/s00441-018-2884-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 07/04/2018] [Indexed: 12/17/2022]
Abstract
Articular cartilage defect remains the most challenging joint disease due to limited intrinsic healing capacity of the cartilage that most often progresses to osteoarthritis. In recent years, stem cell therapy has evolved as therapeutic strategies for articular cartilage regeneration. However, a number of studies have shown that therapeutic efficacy of stem cell transplantation is attributed to multiple secreted factors that modulate the surrounding milieu to evoke reparative processes. This systematic review and meta-analysis aim to evaluate and compare the therapeutic efficacy of stem cell and secretome in articular cartilage regeneration in animal models. We systematically searched the PubMed, CINAHL, Cochrane Library, Ovid Medline and Scopus databases until August 2017 using search terms related to stem cells, cartilage regeneration and animals. A random effect meta-analysis of the included studies was performed to assess the treatment effects on new cartilage formation on an absolute score of 0-100% scale. Subgroup analyses were also performed by sorting studies independently based on similar characteristics. The pooled analysis of 59 studies that utilized stem cells significantly improved new cartilage formation by 25.99% as compared with control. Similarly, the secretome also significantly increased cartilage regeneration by 26.08% in comparison to the control. Subgroup analyses revealed no significant difference in the effect of stem cells in new cartilage formation. However, there was a significant decline in the effect of stem cells in articular cartilage regeneration during long-term follow-up, suggesting that the duration of follow-up is a predictor of new cartilage formation. Secretome has shown a similar effect to stem cells in new cartilage formation. The risk of bias assessment showed poor reporting for most studies thereby limiting the actual risk of bias assessment. The present study suggests that both stem cells and secretome interventions improve cartilage regeneration in animal trials. Graphical abstract ᅟ.
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Use of Self-Assembling Peptides to Enhance Stem Cell Function for Therapeutic Angiogenesis. Stem Cells Int 2018; 2018:4162075. [PMID: 30008751 PMCID: PMC6020535 DOI: 10.1155/2018/4162075] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 05/21/2018] [Indexed: 12/12/2022] Open
Abstract
The use of nanomaterials for biomedical applications has become a promising field in regenerative medicine. Self-assembling peptides (SAPs) have been proposed as a good candidate because they are able to self-assemble into stable hydrogels and interact with cells or molecules when combined together. This in turn can lead to the improved survival or action of cells or molecules to obtain the desired effects. In this study, we investigated whether the combination of mesenchymal stem cells (MSCs) with SAPs could improve angiogenesis in ischemic hindlimbs of rats compared to MSC or SAP treatment alone. The combination of MSCs and SAPs showed an overall higher expression of angiogenesis markers on fluorescent immunohistochemical analysis and a lower degree of fibrosis and cell apoptosis, which in turn led to an overall tendency for improved perfusion of the ischemic hindlimbs. Finally, SAPs also showed the ability to recruit endogenous host MSCs into the site of action, especially when modified to incorporate substance P as a functional motif, which when injected with exogenous MSCs, allowed for the dual presence of MSCs at the site of action. Overall, these results suggest that SAPs can be applied with stem cells to potentiate angiogenesis, with potential therapeutic application in vascular diseases.
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Xing D, Kwong J, Yang Z, Hou Y, Zhang W, Ma B, Lin J. Intra-articular injection of mesenchymal stem cells in treating knee osteoarthritis: a systematic review of animal studies. Osteoarthritis Cartilage 2018; 26:445-461. [PMID: 29427723 DOI: 10.1016/j.joca.2018.01.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 01/09/2018] [Accepted: 01/13/2018] [Indexed: 02/02/2023]
Abstract
PURPOSE Mesenchymal stem cells (MSCs) injection has emerged as a novel treatment for knee osteoarthritis (KOA) but with inconsistent results in the experimental studies. Thus, the purpose of the present study is to evaluate the preclinical animal studies of MSCs injection for KOA and to determine the evidence for a role for MSCs in further clinical trials. METHODS A systematic search of KOA animal studies published through Aug 2017 was conducted using the PubMed, Embase and Web of science. Criteria for eligibility were animal studies assessing the therapeutic effects of MSCs intra-articular injection to animals with KOA. The methodological quality of included studies was assessed by the SYRCLE tool for assessing risk of bias in animal intervention studies. Descriptive synthesis was performed. Evidence quality was evaluated based on the Confidence in the Evidence from Reviews of Qualitative research (CERQual) tool. RESULTS Twenty-three KOA animal studies were eligible for inclusion. According to the SYRCLE's tool, all included studies had high risk of bias. Between-study heterogeneity was substantial. The included studies varied in terms of species, modeling methods, MSCs origin, treatment timing, injections frequency, transplantation type and dose of MSCs. The following outcomes, gross morphology, histological analysis, immunohistochemical analysis, radiological evaluation or behavior analysis, were reported in the primary studies. For all outcomes, the evidence quality was low or very low. CONCLUSIONS We do not have absolute confidence to recommend use MSCs injection for KOA clinical trials. Based on the internal and external validity of current animal studies, high quality experimental studies and efforts for effective translation from preclinical studies to clinical trials are still required.
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Affiliation(s)
- D Xing
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China; Arthritis Institute, Peking University, Beijing, China
| | - J Kwong
- Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Z Yang
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China; Arthritis Institute, Peking University, Beijing, China
| | - Y Hou
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China; Arthritis Institute, Peking University, Beijing, China
| | - W Zhang
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China; Arthritis Institute, Peking University, Beijing, China
| | - B Ma
- Evidence-Based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Gansu, China; Chinese GRADE Center, Gansu, China.
| | - J Lin
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China; Arthritis Institute, Peking University, Beijing, China.
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Li Y, Cao J, Han S, Liang Y, Zhang T, Zhao H, Wang L, Sun Y. ECM based injectable thermo-sensitive hydrogel on the recovery of injured cartilage induced by osteoarthritis. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2018; 46:152-160. [PMID: 29575932 DOI: 10.1080/21691401.2018.1452752] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Intra-articular injection of anti-inflammatory drugs can be a promising strategy for recovery of injured articular cartilage. We prepared a series of injectable thermo-sensitive composite hydrogels, composed of Pluronic F127, glycosaminoglycan (GAG) and bone morphogenetic protein (BMP-2), which was designed to mimic extracellular matrix (ECM). The rheological properties and dissolution rate of composite hydrogels containing chondroitin sulfate or with different hyaluronic acid molecular mass (10k, 90k, 800k) were investigated. Meanwhile, bovine serum albumin (BSA) or FITC-BSA was chosen as model drug loaded into PF/GAG hydrogels to study their sustained release behavior in vitro. The results showed that hydrogels could maintain shapes for more than 16 days and the release rate of BSA in PF/GAG composite gels was much slower than in PF127 gels, due to the affinity between BSA and GAG. Furthermore, increasing the molecular weight of hyaluronic acid correspondingly increased hydrogel dissolution rate and BSA release in the hydrogels. Subsequently, MTT experiments were performed to investigate the toxicity of the hydrogels on mouse pre-osteoblast cell MC3T3-E1. In vivo anti-inflammation results showed that PF/GAG@BMP-2 composite hydrogels had the most efficient efficacy on recovery of injured cartilage, which is induced by osteoarthritis, compared to the control groups (PF127@BMP-2 or BMP-2 saline solution).
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Affiliation(s)
- Yitong Li
- a Department of Pharmaceutics , School of Pharmacy, Qingdao University , Qingdao , China
| | - Jie Cao
- a Department of Pharmaceutics , School of Pharmacy, Qingdao University , Qingdao , China
| | - Shangcong Han
- a Department of Pharmaceutics , School of Pharmacy, Qingdao University , Qingdao , China
| | - Yan Liang
- a Department of Pharmaceutics , School of Pharmacy, Qingdao University , Qingdao , China
| | - Tingting Zhang
- a Department of Pharmaceutics , School of Pharmacy, Qingdao University , Qingdao , China
| | - Han Zhao
- b Department of Pathology , Affiliated Hospital of Qingdao University , Qingdao , China
| | - Libin Wang
- c Collaborative Innovation Center for Marine Biomass Fibers, Materials and Textiles of Shandong Province , Qingdao University , Qingdao , China
| | - Yong Sun
- a Department of Pharmaceutics , School of Pharmacy, Qingdao University , Qingdao , China
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Kim JE, Lee JH, Kim SH, Jung Y. Skin Regeneration with Self-Assembled Peptide Hydrogels Conjugated with Substance P in a Diabetic Rat Model. Tissue Eng Part A 2018; 24:21-33. [DOI: 10.1089/ten.tea.2016.0517] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Affiliation(s)
- Ji Eun Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
- Biomaterials Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Jung Hwa Lee
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
- Biomaterials Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Soo Hyun Kim
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
- Biomaterials Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
- Department of Biomedical Engineering, University of Science and Technology (UST), Seoul, Republic of Korea
| | - Youngmee Jung
- Biomaterials Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
- Department of Biomedical Engineering, University of Science and Technology (UST), Seoul, Republic of Korea
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Therapeutic Benefit for Late, but Not Early, Passage Mesenchymal Stem Cells on Pain Behaviour in an Animal Model of Osteoarthritis. Stem Cells Int 2017; 2017:2905104. [PMID: 29434641 PMCID: PMC5757143 DOI: 10.1155/2017/2905104] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 09/07/2017] [Indexed: 12/29/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have a therapeutic potential for the treatment of osteoarthritic (OA) joint pathology and pain. The aims of this study were to determine the influence of a passage number on the effects of MSCs on pain behaviour and cartilage and bone features in a rodent model of OA. Methods Rats underwent either medial meniscal transection (MNX) or sham surgery under anaesthesia. Rats received intra-articular injection of either 1.5 × 106 late passage MSCs labelled with 10 μg/ml SiMAG, 1.5 × 106 late passage mesenchymal stem cells, the steroid Kenalog (200 μg/20 μL), 1.5 × 106 early passage MSCs, or serum-free media (SFM). Sham-operated rats received intra-articular injection of SFM. Pain behaviour was quantified until day 42 postmodel induction. Magnetic resonance imaging (MRI) was used to localise the labelled cells within the knee joint. Results Late passage MSCs and Kenalog attenuated established pain behaviour in MNX rats, but did not alter MNX-induced joint pathology at the end of the study period. Early passage MSCs exacerbated MNX-induced pain behaviour for up to one week postinjection and did not alter joint pathology. Conclusion Our data demonstrate for the first time the role of a passage number in influencing the therapeutic effects of MSCs in a model of OA pain.
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Mei L, Shen B, Xue J, Liu S, Ma A, Liu F, Shao H, Chen J, Chen Q, Liu F, Ying Y, Ling P. Adipose tissue–derived stem cells in combination with xanthan gum attenuate osteoarthritis progression in an experimental rat model. Biochem Biophys Res Commun 2017; 494:285-291. [DOI: 10.1016/j.bbrc.2017.10.039] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 10/07/2017] [Indexed: 12/24/2022]
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Extracorporeal Shock Wave Rebuilt Subchondral Bone In Vivo and Activated Wnt5a/Ca 2+ Signaling In Vitro. BIOMED RESEARCH INTERNATIONAL 2017; 2017:1404650. [PMID: 29164146 PMCID: PMC5661093 DOI: 10.1155/2017/1404650] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Revised: 08/14/2017] [Accepted: 08/29/2017] [Indexed: 12/27/2022]
Abstract
Background This study aimed to identify the optimal extracorporeal shock wave (ESW) intensity and to investigate its effect on subchondral bone rebuilt in vivo and Wnt5a/Ca2+ signaling in vitro using an osteoarthritis (OA) rat model and bone marrow mesenchymal stem cells (BMMSCs), respectively. Methods OA rats treated with (OA + ESW group) or without (OA group) ESW (n = 12/group) were compared with healthy controls (control group, n = 12). Gait patterns and subchondral trabecular bone changes were measured. Western blot and quantitative real-time polymerase chain reaction detected protein expression and gene transcription, respectively. Results The gait disturbances of OA + ESW group were significantly improved compared with the OA group at 6th and 8th weeks. The micro-CT analysis indicated that the BMD, BSV/BV, BV/TV, Tr.S, and Tr.Th are significantly different between OA group and OA + ESW group. Expression of Wnt5a was increased rapidly after ESW treatment at 0.6 bar and peaked after 30 min. Conclusions ESW were positive for bone remodeling in joint tibial condyle subchondral bone of OA rat. ESW prevented histological changes in OA and prevented gait disturbance associated with OA progression. Optimal intensity of ESW induced changes in BMMSCs via activation of the Wnt5a/Ca2+ signaling pathway.
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