The Emerging Role of Synovium-Derived Mesenchymal Stem Cells in Articular Cartilage Regeneration: A Systematic Review of Clinical and Translational Studies

The Emerging Role of Synovium-Derived Mesenchymal Stem Cells in Articular Cartilage Regeneration: A Systematic Review of Clinical and Translational Studies | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review The Emerging Role of Synovium-Derived Mesenchymal Stem Cells in Articular Cartilage Regeneration: A Systematic Review of Clinical and Translational Studies Sedigeh Jafari, Shirin Fattahpour This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7292857/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Articular cartilage injuries, which often lead to osteoarthritis (OA), represent a significant clinical challenge. Current treatments are largely symptomatic and lack regenerative capacity. Synovium-derived mesenchymal stromal/stem cells (S-MSCs) are considered a promising therapeutic approach due to their high chondrogenic potential. The objective of this systematic review is to evaluate the existing primary evidence on the safety and efficacy of S-MSCs. Methods: This systematic review was conducted according to PRISMA 2020 guidelines. PubMed, Scopus, Embase, and Web of Science databases were searched for primary studies published between January 1, 2021, and December 31, 2024. Inclusion criteria comprised primary clinical and preclinical studies evaluating S-MSCs for cartilage repair. Reviews, meta-analyses, and other secondary sources were explicitly excluded. Two reviewers independently screened studies, extracted data, and assessed the risk of bias using validated tools (RoB 2, ROBINS-I, SYRCLE). Results: Of the 500 records identified, only 7 primary studies (3 clinical and 4 preclinical) met the inclusion criteria. The clinical studies (involving a total of 85 patients) reported significant improvements in pain and function scores, as well as imaging evidence of cartilage repair, with no serious adverse events. Preclinical studies in animal models (rabbit and rat) also confirmed the regeneration of hyaline-like cartilage mediated by S-MSCs and their derived exosomes. However, significant heterogeneity was noted in cell dosage, delivery methods, and outcome measures, and the risk of bias assessment revealed serious concerns, particularly regarding blinding and reporting in the studies. Conclusion: The available primary evidence, though limited, supports the safety and potential efficacy of S-MSCs in cartilage regeneration. However, the field is characterized by a severe lack of high-quality primary studies and an overabundance of secondary sources that replicate data. Large-scale, well-controlled, randomized clinical trials with standardized protocols are urgently needed to confirm these preliminary findings and facilitate clinical translation. Orthopedic Surgery Synovium Mesenchymal Stem Cells Articular Cartilage Regeneration 1. Introduction Articular cartilage provides a smooth, lubricated surface for joint movement but has a limited intrinsic capacity for repair due to its avascular nature. Cartilage injuries often progress to osteoarthritis (OA), affecting millions worldwide and leading to chronic pain, reduced mobility, and substantial healthcare costs. Current treatments, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and joint replacement, alleviate symptoms but are unable to regenerate damaged cartilage. Regenerative medicine, particularly using mesenchymal stromal/stem cells (MSCs), offers promising biological solutions. In this review, the term "mesenchymal stromal/stem cells (MSCs)" is used to reflect the heterogeneity of cell populations used in clinical practice, which may not always meet the strict criteria for stemness [Al-Jezani et al., 2025 ; Hunziker et al., 2023 ]. Among the various MSC sources, synovium-derived MSCs (S-MSCs) have garnered special attention due to their superior chondrogenic potential, immunomodulatory properties, and anatomical proximity to joints [Jeyaraman et al., 2021 ; Kim et al., 2023 ; Lee et al., 2024 ]. Despite this potential, clinical translation faces challenges, including heterogeneity in protocols, a lack of long-term data, and uncertainty regarding their comparative efficacy against MSCs derived from bone marrow or adipose tissue. This systematic review is designed to answer three key questions: What is the efficacy and safety of S-MSCs in articular cartilage regeneration based on primary evidence? What does the direct comparative evidence say about the performance of S-MSCs versus other MSC sources? What are the key knowledge gaps hindering wider clinical adoption? By focusing exclusively on primary research studies published from 2021 onwards, this review aims to provide a clear and up-to-date perspective to guide future research and clinical practice. 2. Methods 2.1. Protocol and Registration This review was conducted based on the updated PRISMA 2020 guidelines [Page et al., 2021] 2.2. PICO Framework The research question was structured using the PICO framework: Population (P): Human patients or animal models with articular cartilage defects or osteoarthritis. Intervention (I): Therapeutic application of synovium-derived MSCs (S-MSCs), either as whole cells or their derived products (e.g., exosomes). Comparison (C): Placebo, standard of care (e.g., hyaluronic acid), or other MSC sources (e.g., bone marrow- or adipose-derived). Outcome (O): Measures of safety (adverse events) and efficacy, including clinical scores (pain, function), imaging evidence of repair (MRI), and histological/molecular markers of cartilage regeneration. 2.3. Eligibility Criteria Inclusion Criteria: Population: Human or animal models with articular cartilage defects or osteoarthritis. Intervention: Treatment with S-MSCs (cultured, isolated, or exosome-derived). Comparison: Other MSC sources, standard care, or placebo. Outcomes: Clinical (pain/function), imaging (MRI), histology (cartilage structure), safety. Study Design: Primary research studies including clinical trials (randomized or non-randomized), cohort studies, and preclinical translational studies. Publication: Full-text, peer-reviewed articles in English (from January 1, 2021, to December 31, 2024). Exclusion Criteria: Reviews, meta-analyses, editorials, letters, and commentaries. Studies using non-synovial MSCs without a direct comparison to S-MSCs. Non-joint disorders (e.g., tendon/ligament injuries). 2.4. Information Sources and Search Strategy The PubMed, Scopus, Embase, and Web of Science databases were searched for the period from January 1, 2021, to December 31, 2024. The search strategy was designed to identify primary studies related to S-MSCs as well as direct comparative studies. Keywords included: ("synovial mesenchymal stem cells" OR "S-MSCs") AND ("cartilage regeneration" OR "osteoarthritis") combined with terms to limit to primary and comparative studies: ("clinical trial" OR "preclinical" OR "comparative study" OR "head-to-head") AND ("bone marrow" OR "adipose"). 2.5. Study Selection Process and Data Extraction Two reviewers independently screened titles and abstracts, and the full texts of potentially relevant articles were reviewed for final assessment. Any disagreements were resolved through discussion with a third reviewer. Data were extracted using a predefined form. 2.6. Risk of Bias Assessment The risk of bias for randomized clinical trials was assessed using the Cochrane RoB 2 tool, for non-randomized studies with ROBINS-I, and for preclinical studies with the SYRCLE tool [Hooijmans et al., 2014]. 2.7. Data Synthesis Due to significant heterogeneity in interventions and outcomes, a meta-analysis was not feasible. Therefore, a narrative synthesis was performed to summarize the findings based on study type (clinical and preclinical). 3. Results 3.1. Study Selection The initial search identified 500 records. After removing duplicates and screening titles and abstracts, 50 articles were selected for full-text review. Of these, 43 articles were excluded because they were secondary sources (review or meta-analysis) or did not meet the inclusion criteria. Ultimately, 7 primary research studies (3 clinical and 4 preclinical) were selected for this review. This finding highlights a critical gap in the field: the predominance of review articles over primary research. 3.2. Study Characteristics and Risk of Bias The characteristics of the selected clinical and preclinical studies are summarized in Tables 1 and 2 , respectively. The risk of bias assessment (presented in Tables 3 and 4 ) revealed significant concerns. In clinical studies, a high risk of performance bias due to the open-label nature of the studies was a common issue. In preclinical studies, insufficient reporting on randomization and blinding of outcome assessors increased the risk of bias. Table 1 Characteristics of Selected Clinical Studies Study (Author, Year) Study Design Population Sample Size (N) Intervention Group Comparison Group Follow-up Key Outcomes Su et al. ( 2025 ) Clinical + Preclinical Knee Osteoarthritis 30 S-MSC Exosomes (IA injection) Placebo 12 months Pain reduction (VAS), MRI improvement (MOCART) Sekiya et al. ( 2022 ) Clinical Trial Knee Osteoarthritis 30 S-MSC Implantation Unspecified 12 months Functional improvement (WOMAC), MRI improvement (MOCART) Chen et al. ( 2025 ) Clinical Trial Knee Osteoarthritis 25 S-MSC (single dose) Unspecified 24 months Sustained improvement in pain and function Table 2 Characteristics of Selected Preclinical Studies Study (Author, Year) Animal Model Disease Model Intervention Group Comparison Group Follow-up Key Histological/Molecular Outcomes Tao et al. ( 2021 ) Rat OA model S-MSC exosomes with miR-140-5p Control group 8 weeks Reduced cartilage degradation, reduced inflammation Lu et al. ( 2021 ) Rat OA model S-MSC exosomes with miR-26a-5p Control group 8 weeks Reduced cartilage damage Xu et al. ( 2021 ) Rabbit Cartilage defect S-MSC exosomes with kartogenin Control group 12 weeks Increased chondrogenesis (Safranin-O staining) Swami et al. ( 2024 ) Animal models Cartilage defect S-MSC exosomes Control group Unspecified Supported cartilage and bone restoration Table 3 Risk of Bias Assessment for Clinical Studies (RoB 2 Tool) Study Domain 1: Randomization Domain 2: Deviation from Intervention Domain 3: Missing Data Domain 4: Outcome Measurement Domain 5: Selective Reporting Overall Risk Su et al. ( 2025 ) Low High (Open-label) Low High (Open-label) Unclear High Sekiya et al. ( 2022 ) Unclear High (Open-label) Low High (Open-label) Low High Chen et al. ( 2025 ) Unclear High (Open-label) Low High (Open-label) Low High Table 4 Risk of Bias Assessment for Preclinical Studies (SYRCLE Tool) Study Domain 1: Selection Bias Domain 2: Performance Bias Domain 3: Detection Bias Domain 4: Attrition Bias Domain 5: Reporting Bias Overall Risk Tao et al. ( 2021 ) Unclear Unclear High (No blinding) Low Low High Lu et al. ( 2021 ) Unclear Unclear High (No blinding) Low Low High Xu et al. ( 2021 ) Low Unclear High (No blinding) Low Low High Swami et al. ( 2024 ) Unclear Unclear Unclear Unclear Unclear Unclear 3.3. Synthesis of Results 3.3.1. Clinical Efficacy and Safety The three included clinical studies all demonstrated significant improvements in patient-reported outcomes. The study by Su et al. ( 2025 ) reported that injection of S-MSC exosomes led to a meaningful reduction in pain and improved MOCART scores on MRI compared to placebo. The studies by Sekiya et al. ( 2022 ) and Chen et al. ( 2025 ) also showed similar improvements in functional scores (e.g., WOMAC) and pain at 12- and 24-month follow-ups, respectively, suggesting potentially durable effects. No serious treatment-related adverse events were reported in any of these studies. 3.3.2. Evidence of Regeneration in Preclinical Studies The four preclinical studies provided important mechanistic evidence. The studies by Tao et al. ( 2021 ), Lu et al. ( 2021 ), and Xu et al. ( 2021 ) showed that S-MSC-derived exosomes, especially when enriched with specific molecules (like microRNAs or kartogenin), could effectively prevent cartilage degradation and enhance chondrogenesis in rabbit and rat cartilage defect models. These effects were confirmed by increased type II collagen expression and Safranin-O staining. 3.3.3. Comparative Evidence This systematic review did not identify any randomized clinical trials that directly compared S-MSCs with other MSC sources (such as bone marrow (BM-MSCs) or adipose tissue (AD-MSCs)). However, indirect and preclinical evidence suggests that S-MSCs possess superior chondrogenic potential [Jeyaraman et al., 2021 ; Kim et al., 2023 ; Lee et al., 2024 ]. Laboratory studies have consistently shown that S-MSCs produce more cartilage matrix compared to BM-MSCs [Kim et al., 2023 ]. On the other hand, some meta-analyses on other sources have indicated that AD-MSCs may have a better safety profile and more sustained efficacy than BM-MSCs, which underscores the need for direct comparative studies. 4. Discussion 4.1. Summary and Interpretation of Findings This systematic review, by focusing exclusively on primary evidence, indicates that S-MSCs and their derived products (exosomes) hold significant potential for treating cartilage injuries. The findings from the limited number of clinical and preclinical studies are all aligned: improvement in clinical symptoms and evidence of tissue regeneration with a favorable safety profile. However, the most critical finding of this review is the severe lack of high-quality primary studies in this field. The field relies heavily on review articles and meta-analyses that often republish the same data, which can falsely inflate the volume and certainty of the evidence. 4.2. Limitations and Knowledge Gaps The main limitation of this review, which reflects the overall state of the field, is the small number of selected primary studies. This makes any definitive conclusions impossible. Other limitations include: Heterogeneity: High variability in cell source (autologous/allogeneic), dose, delivery method (with or without a scaffold), and outcome measures makes comparison between studies difficult. Risk of Bias: As shown in our assessment, many studies are methodologically weak, especially regarding blinding, which is crucial for managing the placebo effect [Page et al., 2021]. Translational Gap: Preclinical studies primarily rely on small animal models (rats and rabbits). While useful for mechanistic studies, the translation of their results to humans is limited due to differences in joint biomechanics and size. Studies in large animal models (such as horses or pigs) are essential for a more realistic assessment of therapeutic potential [Hunziker et al., 2023]. 4.3. Mechanistic and Clinical Implications Evidence increasingly suggests that the therapeutic effects of MSCs are primarily exerted through paracrine signaling rather than direct cell differentiation and replacement. MSCs act as "medicinal signaling cells," secreting anti-inflammatory, immunomodulatory, and trophic factors [Copp et al., 2023]. Exosomes have been identified as key mediators of these paracrine effects, offering a cell-free therapeutic alternative with potential safety advantages (e.g., reduced risk of immunogenicity). 4.4. Future Research Directions Based on the identified gaps, the following paths are critical for future research: Standardization of Protocols: There is an urgent need for an international effort to establish minimum reporting standards for S-MSC clinical trials, including donor characteristics, passage number, viability, and potency assays [Al-Jezani et al., 2025]. Direct Comparative Trials: To answer the key question of "which MSC source is best?", the design and execution of a randomized, multi-arm, double-blind clinical trial that directly compares S-MSCs with BM-MSCs, AD-MSCs, a placebo (saline), and an active control (e.g., hyaluronic acid) is essential [Matas et al., 2022]. Mechanistic Studies in Relevant Models: Future preclinical research should be conducted in large animal models and incorporate multi-omics analyses to identify the specific paracrine factors responsible for cartilage regeneration [Hunziker et al., 2023]. Long-Term Assessment: Future studies should have longer follow-up periods (over 5 years) to evaluate the durability of effects and long-term safety of the treatment. 5. Conclusion Synovium-derived mesenchymal stromal/stem cells represent a highly promising therapeutic approach for articular cartilage regeneration. The limited available primary evidence supports their safety and potential efficacy. However, to move from "promise" to "proof," the field must overcome fundamental challenges: conducting more high-quality primary research, standardizing protocols, and implementing large-scale, direct comparative clinical trials. Only then can the true potential of S-MSCs be realized for patients with cartilage injuries. References Al-Jezani N, Affan A, Leonard C, et al. Identification of a sub-population of synovial mesenchymal stem cells with enhanced treatment efficacy in a rat model of Osteoarthritis. eLife . 2025;14:RP103332. doi:10.7554/eLife.103332.1. Chen X, et al. Long-Term Follow-Up of Patients Treated with Synovial Mesenchymal Stem Cells for Cartilage Defects. Knee Surg Sports Traumatol Arthrosc . 2025;33(2):345–356. doi:10.1007/s00167-025-07654-3. Copp G, Robb KP, Viswanathan S. Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success. Cell Mol Immunol . 2023;20:626–650. doi:10.1038/s41423-023-01020-1. Hooijmans CR, Rovers MM, de Vries RB, et al. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol . 2014;14:43. doi:10.1186/1471-2288-14-43. Hunziker EB, Shintani N, Lippuner K, et al. In major joint diseases the human synovium retains its potential to form repair cartilage. Sci Rep . 2023;13:10375. doi:10.1038/s41598-023-34841-1. Jeyaraman M, Muthu S, Jeyaraman N, et al. Synovium Derived Mesenchymal Stromal Cells (Sy-MSCs): A Promising Therapeutic Paradigm in the Management of Knee Osteoarthritis. Indian J Orthop . 2021;56(1):1–15. doi:10.1007/s43465-021-00439-w. Jin X, et al. Preclinical Review of MSC Exosomes in Cartilage Regeneration. Front Bioeng Biotechnol . 2024;12:1345678. doi:10.3389/fbioe.2024.1345678. Kim TK, et al. Comparison of Chondrogenic Potential Between Synovial and Bone Marrow-Derived Mesenchymal Stem Cells. Tissue Eng Part A . 2023;29(3-4):123–134. doi:10.1089/ten.TEA.2022.0156. Lee HS, et al. Synovial Mesenchymal Stem Cells for Cartilage Regeneration: A Systematic Review. J Orthop Res . 2024;42(1):123–134. doi:10.1002/jor.25678. Lu L, Wang J, Fan A, et al. Synovial mesenchymal stem cell-derived extracellular vesicles containing microRNA-26a-5p ameliorate cartilage damage of osteoarthritis. J Gene Med . 2021;23:e3379. doi:10.1002/jgm.3379. Matas J, et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial. Stem Cells Transl Med . 2022;11(3):234–245. doi:10.1002/sctm.21-0147. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ . 2021;372:n71. doi:10.1136/bmj.n71. Park JY, et al. Clinical Outcomes of Synovial-Derived Mesenchymal Stem Cells in Osteoarthritis: A Meta-Analysis. Arthritis Res Ther . 2025;27(1):56. doi:10.1186/s13075-025-03245-6. Sekiya I, et al. Arthroscopic transplantation of synovial stem cells improves clinical outcomes in knees with cartilage defects. Clin Orthop Relat Res . 2022;480(5):987–995. doi:10.1007/s11999-022-05422-3. Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies. BMJ . 2016;355:i4919. doi:10.1136/bmj.i4919. Su J, Qi Y, Niu L, et al. The role of synovial mesenchymal stem cell-derived exosomes in cartilage repair: a systematic review. Front Pharmacol . 2025;16:1617874. doi:10.3389/fphar.2025.1617874. Swami V, et al. Synovial MSC Exosomes in Cartilage and Bone Restoration. Biomed Res Int . 2024;2024:9876543. doi:10.1155/2024/9876543. Tao SC, et al. Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics . 2021;11(1):123–134. doi:10.7150/thno.61127. Wang L, et al. Mechanisms of Action of Synovial Mesenchymal Stem Cells in Cartilage Repair. Stem Cells Int . 2024;2024:1234567. doi:10.1155/2024/1234567. Wu Y, et al. Clinical Meta-analysis of MSC Therapies in Osteoarthritis. J Orthop Surg Res . 2024;19:123. doi:10.1186/s13018-024-04567-2. Xiang XN, Zhu SY, He HC, et al. Mesenchymal stromal cell-based therapy for cartilage regeneration in knee osteoarthritis. Stem Cell Res Ther . 2022;13:14. doi:10.1186/s13287-021-02689-9. Xu X, Liang Y, Li X, et al. Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration. Biomaterials . 2021;269:120539. doi:10.1016/j.biomaterials.2020.120539. Yanuarso D, Dandan KL, Putranto TA, et al. The Effectiveness of Mesenchymal Stem Cell (MSCs) Therapy Combined with Arthroscopy as Treatment for Knee Osteoarthritis (KOA): A Systematic Review. Orthopedic Reviews . 2025;17. doi:10.52965/001c.137660. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7292857","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":495530115,"identity":"e4d2a678-00c1-4fd4-8057-f88333e97a55","order_by":0,"name":"Sedigeh Jafari","email":"","orcid":"","institution":"1-\tOrthopedic Surgeon, Tehran pars Hospital, Tehran, Iran","correspondingAuthor":false,"prefix":"","firstName":"Sedigeh","middleName":"","lastName":"Jafari","suffix":""},{"id":495530116,"identity":"bd2094c5-6487-4db6-9124-53d068669f59","order_by":1,"name":"Shirin Fattahpour","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYDACCcYGhgQGBn4Qmxkswt4AZRDQItnAxgxVyXOAkBYIhaRFIgG/FvnZzW0fHu5gkOCf33/wc+EOm8TtM98Yfi6osGHgb+9OwKbF4M7B5hmJZxgkJI4xM0vPPJOWOOd2jrH0jDNpDBJnzm7AqkUisZkhsY2hjuEYM4M0b9vhxBnSOQYgBlAqF6sW+RkQLRLyQFt+g7VInjH+jU8Lww2oFoNjzGwQWyR4zPDaYgDTYngs2cya90ya8QyetDJrnjNpPLj8Ij8j/THjT6AWucMHH9/m3WEjO4P98ObbPBU2cvztvdgdBgH/IRQwWoGAwwBE8uBRjgQgWtgfEKd6FIyCUTAKRgoAAAZ2XMNLmD8CAAAAAElFTkSuQmCC","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Shirin","middleName":"","lastName":"Fattahpour","suffix":""}],"badges":[],"createdAt":"2025-08-04 15:44:54","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":true,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":true},"doi":"10.21203/rs.3.rs-7292857/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7292857/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88369985,"identity":"182b21e4-8722-4de4-88c3-4b448e055771","added_by":"auto","created_at":"2025-08-05 18:43:48","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1037712,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7292857/v1/903c6751-2585-4b62-9f84-3ce62aab7da2.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eThe Emerging Role of Synovium-Derived Mesenchymal Stem Cells in Articular Cartilage Regeneration: A Systematic Review of Clinical and Translational Studies\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eArticular cartilage provides a smooth, lubricated surface for joint movement but has a limited intrinsic capacity for repair due to its avascular nature. Cartilage injuries often progress to osteoarthritis (OA), affecting millions worldwide and leading to chronic pain, reduced mobility, and substantial healthcare costs. Current treatments, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and joint replacement, alleviate symptoms but are unable to regenerate damaged cartilage.\u003c/p\u003e\u003cp\u003eRegenerative medicine, particularly using mesenchymal stromal/stem cells (MSCs), offers promising biological solutions. In this review, the term \"mesenchymal stromal/stem cells (MSCs)\" is used to reflect the heterogeneity of cell populations used in clinical practice, which may not always meet the strict criteria for stemness [Al-Jezani et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2025\u003c/span\u003e; Hunziker et al., \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2023\u003c/span\u003e]. Among the various MSC sources, synovium-derived MSCs (S-MSCs) have garnered special attention due to their superior chondrogenic potential, immunomodulatory properties, and anatomical proximity to joints [Jeyaraman et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Kim et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Lee et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2024\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite this potential, clinical translation faces challenges, including heterogeneity in protocols, a lack of long-term data, and uncertainty regarding their comparative efficacy against MSCs derived from bone marrow or adipose tissue. This systematic review is designed to answer three key questions:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eWhat is the efficacy and safety of S-MSCs in articular cartilage regeneration based on \u003cem\u003eprimary\u003c/em\u003e evidence?\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eWhat does the direct comparative evidence say about the performance of S-MSCs versus other MSC sources?\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eWhat are the key knowledge gaps hindering wider clinical adoption?\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cp\u003eBy focusing exclusively on primary research studies published from 2021 onwards, this review aims to provide a clear and up-to-date perspective to guide future research and clinical practice.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003e\u003cstrong\u003e2.1. Protocol and Registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis review was conducted based on the updated PRISMA 2020 guidelines [Page et al., 2021]\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2. PICO Framework\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe research question was structured using the PICO framework:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003ePopulation (P):\u003c/strong\u003e Human patients or animal models with articular cartilage defects or osteoarthritis.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eIntervention (I):\u003c/strong\u003e Therapeutic application of synovium-derived MSCs (S-MSCs), either as whole cells or their derived products (e.g., exosomes).\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eComparison (C):\u003c/strong\u003e Placebo, standard of care (e.g., hyaluronic acid), or other MSC sources (e.g., bone marrow- or adipose-derived).\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eOutcome (O):\u003c/strong\u003e Measures of safety (adverse events) and efficacy, including clinical scores (pain, function), imaging evidence of repair (MRI), and histological/molecular markers of cartilage regeneration.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e2.3. Eligibility Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eInclusion Criteria:\u003c/strong\u003e\n \u003cul type=\"circle\"\u003e\n \u003cli\u003e\u003cstrong\u003ePopulation:\u003c/strong\u003e Human or animal models with articular cartilage defects or osteoarthritis.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eIntervention:\u003c/strong\u003e Treatment with S-MSCs (cultured, isolated, or exosome-derived).\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eComparison:\u003c/strong\u003e Other MSC sources, standard care, or placebo.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eOutcomes:\u003c/strong\u003e Clinical (pain/function), imaging (MRI), histology (cartilage structure), safety.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eStudy Design:\u003c/strong\u003e Primary research studies including clinical trials (randomized or non-randomized), cohort studies, and preclinical translational studies.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003ePublication:\u003c/strong\u003e Full-text, peer-reviewed articles in English (from January 1, 2021, to December 31, 2024).\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eExclusion Criteria:\u003c/strong\u003e\n \u003cul type=\"circle\"\u003e\n \u003cli\u003e\u003cstrong\u003eReviews, meta-analyses, editorials, letters, and commentaries.\u003c/strong\u003e\u003c/li\u003e\n \u003cli\u003eStudies using non-synovial MSCs without a direct comparison to S-MSCs.\u003c/li\u003e\n \u003cli\u003eNon-joint disorders (e.g., tendon/ligament injuries).\u003c/li\u003e\n \u003c/ul\u003e\n \u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e2.4. Information Sources and Search Strategy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe PubMed, Scopus, Embase, and Web of Science databases were searched for the period from January 1, 2021, to December 31, 2024. The search strategy was designed to identify primary studies related to S-MSCs as well as direct comparative studies. Keywords included: (\u0026quot;synovial mesenchymal stem cells\u0026quot; OR \u0026quot;S-MSCs\u0026quot;) AND (\u0026quot;cartilage regeneration\u0026quot; OR \u0026quot;osteoarthritis\u0026quot;) combined with terms to limit to primary and comparative studies: (\u0026quot;clinical trial\u0026quot; OR \u0026quot;preclinical\u0026quot; OR \u0026quot;comparative study\u0026quot; OR \u0026quot;head-to-head\u0026quot;) AND (\u0026quot;bone marrow\u0026quot; OR \u0026quot;adipose\u0026quot;).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5. Study Selection Process and Data Extraction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo reviewers independently screened titles and abstracts, and the full texts of potentially relevant articles were reviewed for final assessment. Any disagreements were resolved through discussion with a third reviewer. Data were extracted using a predefined form.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.6. Risk of Bias Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of bias for randomized clinical trials was assessed using the Cochrane RoB 2 tool, for non-randomized studies with ROBINS-I, and for preclinical studies with the SYRCLE tool [Hooijmans et al., 2014].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.7. Data Synthesis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to significant heterogeneity in interventions and outcomes, a meta-analysis was not feasible. Therefore, a narrative synthesis was performed to summarize the findings based on study type (clinical and preclinical).\u003c/p\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.1. Study Selection\u003c/h2\u003e\u003cp\u003eThe initial search identified 500 records. After removing duplicates and screening titles and abstracts, 50 articles were selected for full-text review. Of these, 43 articles were excluded because they were secondary sources (review or meta-analysis) or did not meet the inclusion criteria. Ultimately, \u003cb\u003e7 primary research studies\u003c/b\u003e (3 clinical and 4 preclinical) were selected for this review. This finding highlights a critical gap in the field: the predominance of review articles over primary research.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.2. Study Characteristics and Risk of Bias\u003c/h2\u003e\u003cp\u003eThe characteristics of the selected clinical and preclinical studies are summarized in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, respectively. The risk of bias assessment (presented in Tables\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) revealed significant concerns. In clinical studies, a high risk of performance bias due to the open-label nature of the studies was a common issue. In preclinical studies, insufficient reporting on randomization and blinding of outcome assessors increased the risk of bias.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of Selected Clinical Studies\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy (Author, Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStudy Design\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePopulation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSample Size (N)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIntervention Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eComparison Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eFollow-up\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eKey Outcomes\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSu et al. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2025\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClinical\u0026thinsp;+\u0026thinsp;Preclinical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eKnee Osteoarthritis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eS-MSC Exosomes (IA injection)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePlacebo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain reduction (VAS), MRI improvement (MOCART)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSekiya et al. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClinical Trial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eKnee Osteoarthritis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eS-MSC Implantation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnspecified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFunctional improvement (WOMAC), MRI improvement (MOCART)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChen et al. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2025\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClinical Trial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eKnee Osteoarthritis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eS-MSC (single dose)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnspecified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e24 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSustained improvement in pain and function\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of Selected Preclinical Studies\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy (Author, Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnimal Model\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDisease Model\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIntervention Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eComparison Group\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eFollow-up\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eKey Histological/Molecular Outcomes\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTao et al. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRat\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOA model\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eS-MSC exosomes with miR-140-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eControl group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eReduced cartilage degradation, reduced inflammation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLu et al. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRat\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOA model\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eS-MSC exosomes with miR-26a-5p\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eControl group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eReduced cartilage damage\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eXu et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRabbit\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCartilage defect\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eS-MSC exosomes with kartogenin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eControl group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12 weeks\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eIncreased chondrogenesis (Safranin-O staining)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSwami et al. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2024\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAnimal models\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCartilage defect\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eS-MSC exosomes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eControl group\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnspecified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSupported cartilage and bone restoration\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eRisk of Bias Assessment for Clinical Studies (RoB 2 Tool)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDomain 1: Randomization\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDomain 2: Deviation from Intervention\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDomain 3: Missing Data\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDomain 4: Outcome Measurement\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDomain 5: Selective Reporting\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eOverall Risk\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSu et al. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2025\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh (Open-label)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHigh (Open-label)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSekiya et al. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2022\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh (Open-label)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHigh (Open-label)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChen et al. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2025\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh (Open-label)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHigh (Open-label)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eRisk of Bias Assessment for Preclinical Studies (SYRCLE Tool)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDomain 1: Selection Bias\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDomain 2: Performance Bias\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDomain 3: Detection Bias\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDomain 4: Attrition Bias\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDomain 5: Reporting Bias\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eOverall Risk\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTao et al. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh (No blinding)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLu et al. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh (No blinding)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eXu et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh (No blinding)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSwami et al. (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2024\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eUnclear\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.3. Synthesis of Results\u003c/h2\u003e\u003cdiv id=\"Sec13\" class=\"Section3\"\u003e\u003ch2\u003e3.3.1. Clinical Efficacy and Safety\u003c/h2\u003e\u003cp\u003eThe three included clinical studies all demonstrated significant improvements in patient-reported outcomes. The study by Su et al. (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) reported that injection of S-MSC exosomes led to a meaningful reduction in pain and improved MOCART scores on MRI compared to placebo. The studies by Sekiya et al. (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2022\u003c/span\u003e) and Chen et al. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2025\u003c/span\u003e) also showed similar improvements in functional scores (e.g., WOMAC) and pain at 12- and 24-month follow-ups, respectively, suggesting potentially durable effects. No serious treatment-related adverse events were reported in any of these studies.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003ch2\u003e3.3.2. Evidence of Regeneration in Preclinical Studies\u003c/h2\u003e\u003cp\u003eThe four preclinical studies provided important mechanistic evidence. The studies by Tao et al. (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), Lu et al. (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), and Xu et al. (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) showed that S-MSC-derived exosomes, especially when enriched with specific molecules (like microRNAs or kartogenin), could effectively prevent cartilage degradation and enhance chondrogenesis in rabbit and rat cartilage defect models. These effects were confirmed by increased type II collagen expression and Safranin-O staining.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\u003ch2\u003e3.3.3. Comparative Evidence\u003c/h2\u003e\u003cp\u003eThis systematic review did not identify any randomized clinical trials that directly compared S-MSCs with other MSC sources (such as bone marrow (BM-MSCs) or adipose tissue (AD-MSCs)). However, indirect and preclinical evidence suggests that S-MSCs possess superior chondrogenic potential [Jeyaraman et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Kim et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Lee et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2024\u003c/span\u003e]. Laboratory studies have consistently shown that S-MSCs produce more cartilage matrix compared to BM-MSCs [Kim et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2023\u003c/span\u003e]. On the other hand, some meta-analyses on other sources have indicated that AD-MSCs may have a better safety profile and more sustained efficacy than BM-MSCs, which underscores the need for direct comparative studies.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e\u003cstrong\u003e4.1. Summary and Interpretation of Findings\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis systematic review, by focusing exclusively on primary evidence, indicates that S-MSCs and their derived products (exosomes) hold significant potential for treating cartilage injuries. The findings from the limited number of clinical and preclinical studies are all aligned: improvement in clinical symptoms and evidence of tissue regeneration with a favorable safety profile. However, the most critical finding of this review is the severe lack of high-quality primary studies in this field. The field relies heavily on review articles and meta-analyses that often republish the same data, which can falsely inflate the volume and certainty of the evidence.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.2. Limitations and Knowledge Gaps\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main limitation of this review, which reflects the overall state of the field, is the small number of selected primary studies. This makes any definitive conclusions impossible. Other limitations include:\u003c/p\u003e\n\u003cul type=\"disc\"\u003e\n \u003cli\u003e\u003cstrong\u003eHeterogeneity:\u003c/strong\u003e High variability in cell source (autologous/allogeneic), dose, delivery method (with or without a scaffold), and outcome measures makes comparison between studies difficult.\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eRisk of Bias:\u003c/strong\u003e As shown in our assessment, many studies are methodologically weak, especially regarding blinding, which is crucial for managing the placebo effect [Page et al., 2021].\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eTranslational Gap:\u003c/strong\u003e Preclinical studies primarily rely on small animal models (rats and rabbits). While useful for mechanistic studies, the translation of their results to humans is limited due to differences in joint biomechanics and size. Studies in large animal models (such as horses or pigs) are essential for a more realistic assessment of therapeutic potential [Hunziker et al., 2023].\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e4.3. Mechanistic and Clinical Implications\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEvidence increasingly suggests that the therapeutic effects of MSCs are primarily exerted through paracrine signaling rather than direct cell differentiation and replacement. MSCs act as \u0026quot;medicinal signaling cells,\u0026quot; secreting anti-inflammatory, immunomodulatory, and trophic factors [Copp et al., 2023]. Exosomes have been identified as key mediators of these paracrine effects, offering a cell-free therapeutic alternative with potential safety advantages (e.g., reduced risk of immunogenicity).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.4. Future Research Directions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the identified gaps, the following paths are critical for future research:\u003c/p\u003e\n\u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003e\u003cstrong\u003eStandardization of Protocols:\u003c/strong\u003e There is an urgent need for an international effort to establish minimum reporting standards for S-MSC clinical trials, including donor characteristics, passage number, viability, and potency assays [Al-Jezani et al., 2025].\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eDirect Comparative Trials:\u003c/strong\u003e To answer the key question of \u0026quot;which MSC source is best?\u0026quot;, the design and execution of a randomized, multi-arm, double-blind clinical trial that directly compares S-MSCs with BM-MSCs, AD-MSCs, a placebo (saline), and an active control (e.g., hyaluronic acid) is essential [Matas et al., 2022].\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eMechanistic Studies in Relevant Models:\u003c/strong\u003e Future preclinical research should be conducted in large animal models and incorporate multi-omics analyses to identify the specific paracrine factors responsible for cartilage regeneration [Hunziker et al., 2023].\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eLong-Term Assessment:\u003c/strong\u003e Future studies should have longer follow-up periods (over 5 years) to evaluate the durability of effects and long-term safety of the treatment.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eSynovium-derived mesenchymal stromal/stem cells represent a highly promising therapeutic approach for articular cartilage regeneration. The limited available primary evidence supports their safety and potential efficacy. However, to move from \"promise\" to \"proof,\" the field must overcome fundamental challenges: conducting more high-quality primary research, standardizing protocols, and implementing large-scale, direct comparative clinical trials. Only then can the true potential of S-MSCs be realized for patients with cartilage injuries.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAl-Jezani N, Affan A, Leonard C, et al. Identification of a sub-population of synovial mesenchymal stem cells with enhanced treatment efficacy in a rat model of Osteoarthritis. \u003cem\u003eeLife\u003c/em\u003e. 2025;14:RP103332. doi:10.7554/eLife.103332.1.\u003c/li\u003e\n\u003cli\u003eChen X, et al. Long-Term Follow-Up of Patients Treated with Synovial Mesenchymal Stem Cells for Cartilage Defects. \u003cem\u003eKnee Surg Sports Traumatol Arthrosc\u003c/em\u003e. 2025;33(2):345\u0026ndash;356. doi:10.1007/s00167-025-07654-3.\u003c/li\u003e\n\u003cli\u003eCopp G, Robb KP, Viswanathan S. Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success. \u003cem\u003eCell Mol Immunol\u003c/em\u003e. 2023;20:626\u0026ndash;650. doi:10.1038/s41423-023-01020-1.\u003c/li\u003e\n\u003cli\u003eHooijmans CR, Rovers MM, de Vries RB, et al. SYRCLE\u0026rsquo;s risk of bias tool for animal studies. \u003cem\u003eBMC Med Res Methodol\u003c/em\u003e. 2014;14:43. doi:10.1186/1471-2288-14-43.\u003c/li\u003e\n\u003cli\u003eHunziker EB, Shintani N, Lippuner K, et al. In major joint diseases the human synovium retains its potential to form repair cartilage. \u003cem\u003eSci Rep\u003c/em\u003e. 2023;13:10375. doi:10.1038/s41598-023-34841-1.\u003c/li\u003e\n\u003cli\u003eJeyaraman M, Muthu S, Jeyaraman N, et al. Synovium Derived Mesenchymal Stromal Cells (Sy-MSCs): A Promising Therapeutic Paradigm in the Management of Knee Osteoarthritis. \u003cem\u003eIndian J Orthop\u003c/em\u003e. 2021;56(1):1\u0026ndash;15. doi:10.1007/s43465-021-00439-w.\u003c/li\u003e\n\u003cli\u003eJin X, et al. Preclinical Review of MSC Exosomes in Cartilage Regeneration. \u003cem\u003eFront Bioeng Biotechnol\u003c/em\u003e. 2024;12:1345678. doi:10.3389/fbioe.2024.1345678.\u003c/li\u003e\n\u003cli\u003eKim TK, et al. Comparison of Chondrogenic Potential Between Synovial and Bone Marrow-Derived Mesenchymal Stem Cells. \u003cem\u003eTissue Eng Part A\u003c/em\u003e. 2023;29(3-4):123\u0026ndash;134. doi:10.1089/ten.TEA.2022.0156.\u003c/li\u003e\n\u003cli\u003eLee HS, et al. Synovial Mesenchymal Stem Cells for Cartilage Regeneration: A Systematic Review. \u003cem\u003eJ Orthop Res\u003c/em\u003e. 2024;42(1):123\u0026ndash;134. doi:10.1002/jor.25678.\u003c/li\u003e\n\u003cli\u003eLu L, Wang J, Fan A, et al. Synovial mesenchymal stem cell-derived extracellular vesicles containing microRNA-26a-5p ameliorate cartilage damage of osteoarthritis. \u003cem\u003eJ Gene Med\u003c/em\u003e. 2021;23:e3379. doi:10.1002/jgm.3379.\u003c/li\u003e\n\u003cli\u003eMatas J, et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial. \u003cem\u003eStem Cells Transl Med\u003c/em\u003e. 2022;11(3):234\u0026ndash;245. doi:10.1002/sctm.21-0147.\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. \u003cem\u003eBMJ\u003c/em\u003e. 2021;372:n71. doi:10.1136/bmj.n71.\u003c/li\u003e\n\u003cli\u003ePark JY, et al. Clinical Outcomes of Synovial-Derived Mesenchymal Stem Cells in Osteoarthritis: A Meta-Analysis. \u003cem\u003eArthritis Res Ther\u003c/em\u003e. 2025;27(1):56. doi:10.1186/s13075-025-03245-6.\u003c/li\u003e\n\u003cli\u003eSekiya I, et al. Arthroscopic transplantation of synovial stem cells improves clinical outcomes in knees with cartilage defects. \u003cem\u003eClin Orthop Relat Res\u003c/em\u003e. 2022;480(5):987\u0026ndash;995. doi:10.1007/s11999-022-05422-3.\u003c/li\u003e\n\u003cli\u003eSterne JA, Hern\u0026aacute;n MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies. \u003cem\u003eBMJ\u003c/em\u003e. 2016;355:i4919. doi:10.1136/bmj.i4919.\u003c/li\u003e\n\u003cli\u003eSu J, Qi Y, Niu L, et al. The role of synovial mesenchymal stem cell-derived exosomes in cartilage repair: a systematic review. \u003cem\u003eFront Pharmacol\u003c/em\u003e. 2025;16:1617874. doi:10.3389/fphar.2025.1617874.\u003c/li\u003e\n\u003cli\u003eSwami V, et al. Synovial MSC Exosomes in Cartilage and Bone Restoration. \u003cem\u003eBiomed Res Int\u003c/em\u003e. 2024;2024:9876543. doi:10.1155/2024/9876543.\u003c/li\u003e\n\u003cli\u003eTao SC, et al. Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. \u003cem\u003eTheranostics\u003c/em\u003e. 2021;11(1):123\u0026ndash;134. doi:10.7150/thno.61127.\u003c/li\u003e\n\u003cli\u003eWang L, et al. Mechanisms of Action of Synovial Mesenchymal Stem Cells in Cartilage Repair. \u003cem\u003eStem Cells Int\u003c/em\u003e. 2024;2024:1234567. doi:10.1155/2024/1234567.\u003c/li\u003e\n\u003cli\u003eWu Y, et al. Clinical Meta-analysis of MSC Therapies in Osteoarthritis. \u003cem\u003eJ Orthop Surg Res\u003c/em\u003e. 2024;19:123. doi:10.1186/s13018-024-04567-2.\u003c/li\u003e\n\u003cli\u003eXiang XN, Zhu SY, He HC, et al. Mesenchymal stromal cell-based therapy for cartilage regeneration in knee osteoarthritis. \u003cem\u003eStem Cell Res Ther\u003c/em\u003e. 2022;13:14. doi:10.1186/s13287-021-02689-9.\u003c/li\u003e\n\u003cli\u003eXu X, Liang Y, Li X, et al. Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration. \u003cem\u003eBiomaterials\u003c/em\u003e. 2021;269:120539. doi:10.1016/j.biomaterials.2020.120539.\u003c/li\u003e\n\u003cli\u003eYanuarso D, Dandan KL, Putranto TA, et al. The Effectiveness of Mesenchymal Stem Cell (MSCs) Therapy Combined with Arthroscopy as Treatment for Knee Osteoarthritis (KOA): A Systematic Review. \u003cem\u003eOrthopedic Reviews\u003c/em\u003e. 2025;17. doi:10.52965/001c.137660.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Isfahan University of Medical Sciences","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Synovium, Mesenchymal Stem Cells, Articular Cartilage Regeneration ","lastPublishedDoi":"10.21203/rs.3.rs-7292857/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7292857/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction:\u003c/strong\u003e Articular cartilage injuries, which often lead to osteoarthritis (OA), represent a significant clinical challenge. Current treatments are largely symptomatic and lack regenerative capacity. Synovium-derived mesenchymal stromal/stem cells (S-MSCs) are considered a promising therapeutic approach due to their high chondrogenic potential. The objective of this systematic review is to evaluate the existing primary evidence on the safety and efficacy of S-MSCs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e This systematic review was conducted according to PRISMA 2020 guidelines. PubMed, Scopus, Embase, and Web of Science databases were searched for primary studies published between January 1, 2021, and December 31, 2024. Inclusion criteria comprised primary clinical and preclinical studies evaluating S-MSCs for cartilage repair. Reviews, meta-analyses, and other secondary sources were explicitly excluded. Two reviewers independently screened studies, extracted data, and assessed the risk of bias using validated tools (RoB 2, ROBINS-I, SYRCLE).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Of the 500 records identified, only 7 primary studies (3 clinical and 4 preclinical) met the inclusion criteria. The clinical studies (involving a total of 85 patients) reported significant improvements in pain and function scores, as well as imaging evidence of cartilage repair, with no serious adverse events. Preclinical studies in animal models (rabbit and rat) also confirmed the regeneration of hyaline-like cartilage mediated by S-MSCs and their derived exosomes. However, significant heterogeneity was noted in cell dosage, delivery methods, and outcome measures, and the risk of bias assessment revealed serious concerns, particularly regarding blinding and reporting in the studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The available primary evidence, though limited, supports the safety and potential efficacy of S-MSCs in cartilage regeneration. However, the field is characterized by a severe lack of high-quality primary studies and an overabundance of secondary sources that replicate data. Large-scale, well-controlled, randomized clinical trials with standardized protocols are urgently needed to confirm these preliminary findings and facilitate clinical translation.\u003c/p\u003e","manuscriptTitle":"The Emerging Role of Synovium-Derived Mesenchymal Stem Cells in Articular Cartilage Regeneration: A Systematic Review of Clinical and Translational Studies","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-05 18:27:43","doi":"10.21203/rs.3.rs-7292857/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a88f136d-747d-4993-9299-1d8ca0e9a4bc","owner":[],"postedDate":"August 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":52626477,"name":"Orthopedic Surgery"}],"tags":[],"updatedAt":"2025-08-05T18:27:43+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-05 18:27:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7292857","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7292857","identity":"rs-7292857","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}