Comparative Analysis of the Therapeutic Potential of Extracellular Vesicles Secreted by Aged and Young Bone Marrow‐Derived Mesenchymal Stem Cells in Osteoarthritis Pathogenesis

Osteoarthritis (OA), a joint disease, burdens global healthcare due to aging and obesity. Recent studies show that extracellular vesicles (EVs) from bone marrow-derived mesenchymal stem cells (BMSCs) contribute to joint homeostasis and OA management. However, the impact of donor age on BMSC-derived EV efficacy remains underexplored. In this study, we investigated EV efficacy from young BMSCs (2-month-old) in mitigating OA, contrasting them with EVs from aged BMSCs (27-month-old). The study used destabilisation of the medial meniscus (DMM) surgery on mouse knee joints to induce accelerated OA. Cartilage degeneration markers and senescence markers' expression levels were investigated in response to EV treatment. The therapeutic impact of EVs on chondrocytes under inflammatory responses was also evaluated. Despite having similar morphologies, EVs from young BMSCs markedly decreased senescence and improved chondroprotection by activating the PTEN pathway while simultaneously suppressing the upregulation of the PI3K/AKT pathways, proving to be more effective than those from older BMSCs in vitro. Furthermore, intraperitoneal injections of EVs from young donors significantly mitigated OA progression by preserving cartilage and reducing synovitis in a surgical OA model using DMM in mice. These findings highlight that donor age as a critical determinant in the therapeutic potential of BMSC-derived EVs for clinical use in OA treatment.