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Mesenchymal stem cell (MSC) therapy is a promising strategy for treating osteoarthritis (OA). However, the inflammatory microenvironment, apoptosis of transplanted cells, and shear forces during direct injection limit the therapeutic efficacy. This study aimed to explore the role of rapamycin combined with human umbilical-cord-derived mesenchymal stem cells (hUMSCs) in OA rabbits  in vivo . OA rabbits received an intra-articular injection of a collagenase solution. Gross observations, X-ray examinations, and histological examinations were performed to detect cartilage degradation levels. The fluorescent membrane dye DiR was used to label hUMSCs. In the combination therapy group, rapamycin was injected into the rabbit knee joint one day post the intra-articular injection of hUMSCs. Bioinformatics and transcriptome profiling of the knee meniscus were used to evaluate the potential molecular mechanisms of the combination therapy. Our study shows that rapamycin combined with hUMSCs significantly ameliorated OA severity  in vivo , enhancing matrix synthesis and promoting cartilage repair. The combination therapy was more efficient than rapamycin or hUMSC treatment alone. Moreover, bioinformatics and transcriptomic analyses revealed that combination therapy might enhance autophagy in chondrocytes, partially by inhibiting the mTOR pathway. Our study indicates that the combination therapy of rapamycin and hUMSCs may promote cartilage repair in OA rabbits through the mTOR pathway and offers a novel approach for OA therapy. Our study provides new evidence to support the use of hUMSCs in combination with rapamycin as a potential candidate for OA treatment.

immunopharmacology and immunotoxicology

Human umbilical-cord-derived mesenchymal stem cells in combination with rapamycin reduce cartilage degradation via inhibition of the  AKT/mTOR  signaling pathway