Platelet-rich plasma-derived exosomes establishing a muscular proregenerative microenvironment through enhancing the viability of fibro-adipogenic progenitors.

Clinical studies have shown a paradox of the usage of platelet-rich plasma (PRP) on treating fatty infiltration (FI) in injured muscles. However, the underlying reason is still unclear, partially owing to unknown effective components and confounders. Here we found that exosomes derived from PRP (thereafter named PRP-exos) most efficiently prevented FI in injured muscles by inhibiting the adipogenesis of fibro-adipogenic progenitors (FAPs). Importantly, we found aging largely impaired the therapeutic effects of PRP-exos. Mechanistically, miRNA cargoes in PRP-exos mediated the effects of PRP-exos on adipogenesis of FAPs as well as FI in injured muscles, of which, hsa-let-7f-5p and hsa-miR-16-5p were the two most important components. TGFBR3 was identified as a new cotarget gene of these two miRNAs and a new regulator to control the adipogenesis of FAPs. The FI in muscles can be significantly reduced after conditional knockout of TGFBR3 in FAPs. In addition, we further investigated that TGFBR3 regulated the activation of ERK-PPARγ pathway through directly inducing the degradation of KRT10, and thus impacted the adipogenesis of FAPs. Interestingly, PRP-exos or these two miRNAs can preserve the viability and promote the proregenerative supporting capacity of FAPs by targeting TGFBR3 to facilitate muscle regeneration. Collectively, our findings identified the effective components in PRP to inhibit FI and support muscle regeneration. Furthermore, the negative influence of aging on clinical applications of PRP cannot be neglected.