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

Abstract

Background and aims

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.

Methods

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.

Results

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.

Conclusions

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.

The translational potential of this article

Our study provides new evidence to support the use of hUMSCs in combination with rapamycin as a potential candidate for OA treatment.

Keywords:

• Human umbilical-cord-derived mesenchymal stem cells
• osteoarthritis
• rapamycin
• combination therapy
• mTOR signaling pathway

Acknowledgements

The authors thank Guangzhou Huateng Biomedical Technology Co., Ltd. for providing the laboratory platforms.

Author contributions

Animal Surgery: YN-B, QQ-C, BF-O, JH-X, and YJ-G. Methodology: YN-B, QQ-C, and BF-O. Formal analysis and investigation: YN-B, JH-X, and BY-C. Writing—original draft preparation: YN-B. Writing—review and editing: YN-B. Funding acquisition: SL-X and YN-B. Resources: SL-X. Supervision: SL-X.

Disclosure statement

No potential conflict of interest was reported by the authors.

Data availability statement

The data used to support the findings of this study are available from the corresponding author upon request.

Additional information

Funding

This work was supported by Basic and Applied Basic Research Project of Guangzhou [grant number 202201010358; 202102020366]; the High-tech Industrialization and Entrepreneurship Team Project Funding of Gaoxin District, Foshan City [grant number 2120197000014], and the Basic and Applied Basic Research Project of GuangDong [grant number 2022A1515110078].