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

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.