Hypoxia Induces HIF-1α Activation in Tendon Stem Cells to Enhance Extracellular Vesicle-Mediated Tendon Repair

Tendon injuries are challenging to treat due to the limited blood supply and low cell density in tendon tissue. Tendon stem cells (TSCs) typically reside in a hypoxic environment (1%-5% oxygen), which may be crucial for their physiological function. In this study, we demonstrated that under hypoxic conditions, TSCs release small extracellular vesicles (sEVs) enriched with functional molecules (mainly noncoding RNAs and proteins). These sEVs significantly reduced fibrosis and inflammation in a rat model of an Achilles tendon injury while enhancing the expression of tendon-related factors, thus promoting tendon healing and improving tissue structure and function. In vitro experiments revealed that hypoxia-induced TSC-derived sEVs not only promoted TSC differentiation but also inhibited the conversion of tenocytes to myofibroblasts and reduced the expression of inflammatory markers in macrophages. These effects were mediated through the HIF-1α/miR-145-3p and miR-504 pathways. Proteomic analysis revealed hypoxia-induced changes in the protein expression profile of sEVs, with differentially expressed proteins closely associated with tendon injury repair. Our findings provide compelling evidence that hypoxia-induced sEVs from TSCs play a pivotal role in tendon repair, offering a robust theoretical basis for the development of therapeutic strategies targeting tendon injuries.