Small extracellular vesicles derived from tendon stem cells promote the healing of injured Achilles tendons by regulating miR-145-3p

The therapeutic role of tendon stem cells (TSCs) in tendon-related injuries has been well documented. Small extracellular vesicles (sEVs) are being increasingly used as new biotherapeutic agents for various diseases. Therefore, the potential function of TSC-sEVs in tendon injury repair warrants further investigation. In this study, we explored the effects of TSC-sEVs on TSC proliferation, migration, and differentiation in vitro in an autocrine manner. We further used a novel exosomal topical treatment with TSC-sEVs loaded with gelatin methacryloyl (GelMA) hydrogel in vivo; we mixed sufficient amounts of TSC-sEVs with GelMA hydrogel to cover the damaged molded Achilles tendon tissue and then exposed them to UV irradiation for coagulation. GelMA loading ensured that TSC-sEVs were slowly released at the injury site over a long period, thereby achieving their full local therapeutic effects. Treatment with TSC-sEVs loaded with GelMA significantly improved the histological score of the regenerated tendon by increasing the tendon expression while inhibiting the formation of excessive ossification and improving the mechanical properties of the tissue. Moreover, miRNA sequencing in TSC-sEVs, TSCs, and TSCs receiving sEVs revealed that TSC-sEVs altered the miRNA expression profile of TSCs, with increased expression of miR-145-3p. In conclusion, our study demonstrates that TSC-sEVs can play a key role in treating tendon injuries and that loading them with GelMA can enhance their effect in vivo. Moreover, miR-145-3p has a major functional role in the effect of TSC-sEVs. This study offers new therapeutic ideas for the local treatment of Achilles tendon injuries using sEVs. STATEMENT OF SIGNIFICANCE: In this study, we demonstrated that TSC-sEVs play a key role in treating tendon injuries and that loading them with GelMA hydrogel can act as a fixation and slow release in vivo. Moreover, it identifies the major functional role of miR-145-3p in the effect of TSCs that were identified and validated by miRNA sequencing. Our study provides a basis for further research on GelMA slow-release assays that have potential clinical applications. It offers new therapeutic ideas for the local treatment of Achilles tendon injuries using TSC-sEVs.