Therapeutic efficacy of extracellular vesicles from hiPSC-derived MSCs in serum-containing and xeno-free media for osteoarthritis treatment.

BACKGROUND: Extracellular vesicles derived from human induced mesenchymal stromal cells (hiEVs) constitute a promising cell-free therapeutic option for osteoarthritis. To facilitate transition to the clinic we evaluated the therapeutic effects of hiEVs for osteoarthritis treatment. Specifically, we compared the efficacy of hiEVs collected from serum-containing and serum-free, PurStem (PS), media in an osteoarthritis mouse model. METHODS: hiEVs were administered via intra-articular injection in a destabilization of the medial meniscus (DMM) mouse model, with or without hydrogel to determine added value of localized application and controlled hiEV-release. Fluorescence imaging was used to monitor the retention of IR780-labeled hiEVs in the joint cavity. Therapeutic effects were evaluated by scoring of damage as well as expression of Mmp13 and Col2, catabolic and anabolic markers respectively, in joint tissues. Subchondral bone changes were assessed with Micro-CT. RESULTS: Fluorescence imaging confirmed that hiEVs remained localized at the injection site without systemic migration. HiEVs demonstrated significant protective effects against joint tissue degeneration in the osteoarthritis DMM mouse model as evidenced by reduced damage scores, decreased Mmp13 expression, and increased Col2 expression independent of the medium used for hiEV collection. The hydrogel alone also showed beneficial therapeutic effects, illustrated by reduced damage scores, increased Col2, and reduced Mmp13 expression. These effects, however, were notably smaller than those achieved with hiEV treatment. Micro-CT analysis further showed that hiEV treatment attenuated DMM-induced subchondral bone sclerosis as reflected by normalization of the bone volume fraction and trabecular structure. CONCLUSIONS: Together, our findings demonstrate that hiEVs from xeno-free conditions effectively prevent cartilage degradation and promote its repair. This paves the way for future clinical translation of hiEV-based therapies as a safe, scalable, and effective approach to treat osteoarthritis.