Distinct Reparative and Immunomodulatory Signatures of Extracellular Vesicles From Human Cartilage-Derived...

BackgroundExtracellular vesicles (EVs) mediate many of the reparative effects of cell-based therapies for osteoarthritis; however, the influence of EV source on cartilage repair and systemic immune responses remains unclear. Cartilage-resident chondroprogenitors represent lineage-biased cell populations with enhanced chondrogenic stability when compared with BM-MSCs and chondrocytes.MethodsEVs were isolated from human BM-MSCs, chondrocytes, fibronectin adhesion assay-derived chondroprogenitors (FAA-CPs), and migratory chondroprogenitors (MCPs) obtained from non-diseased donors. EVs were characterised for size, surface markers, and protein content. Osteoarthritis was induced in Wistar rats using the monosodium iodoacetate model. EVs (40 µg) were administered intra-articularly once weekly for six weeks. Each treatment group included 12 joints, with sham and OA controls. Cartilage repair was assessed by routine histological evaluation, collagen immunohistochemistry and modified Mankin scoring. Systemic immune responses were evaluated using splenic IL-6 and TNF-α expression.ResultsAll EV-treated groups demonstrated improved cartilage morphology compared with controls. EVs derived from cartilage-resident cells consistently promoted superior cartilage repair compared with BM-MSC-derived EVs, with improved proteoglycan retention, collagen type II deposition, and lower modified Mankin scores. FAA-CP and MCP EVs showed comparable reparative profiles and modestly outperformed chondrocyte-derived EVs. BM-MSC EVs exhibited the lowest splenic IL-6 and TNF-α expression, indicating stronger immunomodulatory effects, while cartilage-resident EVs showed immune profiles similar to chondrocytes.ConclusionEV source significantly influences cartilage repair and immunological behaviour in early osteoarthritis. Cartilage-resident cell EVs demonstrate enhanced repair, whereas BM-MSC EVs retain stronger immunomodulatory capacity. These findings support rational EV source selection for cartilage regeneration strategies.