Stem cell-derived small extracellular vesicles containing miR-27b-3p attenuated osteoarthritis by targeting leukaemia inhibitory factor expression of synoviocytes

Abstract: Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been demonstrated to be effective in the treatment of OA, but the precise target cells and response mechanisms are not well characterised. In this study, first, we found that intra-articular injection of human umbilical cord MSC (UCMSC)-derived sEVs (U-sEVs) significantly alleviated mouse OA. Then, U-sEVs were taken up rapidly and preferentially by fibroblast-like synoviocytes (FLSs) in a mouse model. Furthermore, significant increase in miR-27b-3p in FLSs after U-sEV treatment were found by miRNA sequencing, identifying miR-27b-3p as a key cargo of U-sEVs. Bioinformatics and luciferase reporter found that leukaemia inhibitory factor (LIF) is the target gene of miR-27b-3p, and single-cell RNA-sequencing (scRNA-seq) and RNA-sequencing revealed that LIF could directly induce synovitis, possibly by promoting proinflammatory cytokine and MMPs expression. Lastly, both miR-27b-3p and miR-27b-3p-overexpressing U-sEVs inhibit the expression of LIF in FLSs, and accordingly exhibited stronger effects in mitigating synovitis and OA progression compared to control U-sEVs. In conclusion, our results revealed that the main recipient cell of U-sEVs in the joints are FLSs. Mechanistically, miR-27b-3p in U-sEVs inhibited LIF expression of FLSs, and thus inhibited synovitis and delayed OA.