Extracellular Vesicle‐Contained Thrombospondin 1 Retards Age‐Related Degenerative Tendinopathy by Rejuvenating Tendon Stem/Progenitor Cell Senescence

Abstract Advanced age is a major risk factor for age‐related degenerative tendinopathy. During aging, tendon stem/progenitor cell (TSPC) function declines owing to the transition from a normal quiescent state to a senescent state. Extracellular vesicles (EVs) from young stem cells are reported to possess anti‐aging functions. However, it remains unclear whether EVs from young TSPCs (TSPC‐EVs) can rejuvenate senescent TSPCs to delay age‐related degeneration. Here, this study finds that TSPC‐EVs can mitigate the aging phenotypes of senescent TSPCs and maintain their tenogenic capacity. In vitro studies reveal that TSPC‐EVs can reinstall autophagy in senescent TSPCs to alleviate cellular senescence, and that the re‐establishment of autophagy is mediated by the PI3K/AKT pathway. Mechanistically, this study finds that thrombospondin 1, a negative regulator of the PI3K/AKT pathway, is enriched in TSPC‐EVs and can be transported to senescent TSPCs. Moreover, in vivo studies show that the local delivery of TSPC‐EVs can rejuvenate senescent TSPCs and promote their tenogenic differentiation, thereby rescuing tendon regeneration in aged rats. Taken together, TSPC‐EVs as a novel cell‐free approach have promising therapeutic potential for aging‐related degenerative tendinopathy.