报告内容摘要：

Mesenchymal stromal/stem cells (MSCs) are currently evaluated in clinical trials for treatment of cartilage injuries and osteoarthritis. While cell therapy has demonstrated therapeutic efficacy, logistical and operational challenges associated with shipping constrains, storage and proper handling remain. Increasingly, the therapeutic efficacy of MSCs is attributed to the secretion of paracrine factors that exhibit diverse effects including anti-inflammation, angiogenesis, chemoattraction, cell survival, and immunomodulation. Recently, it has emerged that among this wide myriad of factors present in the MSC secretome, exosomes are identified and found to mediate paracrine functions of MSCs in tissue repair and regeneration. Exosomes are a specific class of extracellular vesicles (EVs) that are nano-sized (50-100nm) and function primarily as intercellular communication vehicles to transfer bioactive lipids, nucleic acids (mRNAs and microRNAs) and proteins between cells to elicit biological responses in recipient cells. Importantly, exosomes have been found to mediate the underlying paracrine regenerative and immunomodulatory mechanisms of MSCs in treatment of various diseases in animal studies. Here, we tested the hypothesis that human MSC exosomes may have therapeutic effects in repair of critical-sized osteochondral defects in an immunocompetent rat model. Our results showed that weekly intra-articular injections of MSC exosomes promoted early cellular infiltration and proliferation that facilitated orderly cartilage and subchondral bone regeneration. Analysis of cellular proliferation showed significantly higher numbers of proliferative cell nuclear antigen (PCNA) positive cells in both the synovium and reparative tissue in animals treated with MSC exosomes than in animals treated with saline. Concomitantly, we detected reduced numbers of apoptotic cells in the reparative tissue in animals treated with MSC exosomes. By end of 12 weeks, MSC exosome-treated rats showed a smooth hyaline neocartilage layer and regenerated subchondral bone. On contrary, saline-treated defects showed severe surface irregularity and mostly fibrous/non-cartilaginous tissues with minimal matrix deposition. We also found that MSC exosomes induced polarization of the synovial macrophages with a regenerative M2 phenotype. Importantly, no adverse reactions were observed in all animals. These findings are consistent with our in vitro experiment results that observed enhanced proliferation, migration and matrix synthesis of chondrocytes when treated with MSC exosome. Taken together, our results show that MSC exosomes are safe and effective, and likely mediate cartilage regeneration through multi-faceted mechanisms. Our findings support the future development of human MSC exosomes as a novel off-the-shelf and cell-free therapeutic for cartilage repair.