Exosomal miR-378a-3p derived from keratinocytes inhibits transforming growth factor beta-induced fibroblast activation and attenuates bleomycin-induced skin fibrosis

Abstract

Abstract The association between microRNAs (miRNAs) and the development of skin fibrosis has been established. Consequently, the investigation of miRNA is crucial for the management of cutaneous fibrotic diseases. Recent investigations have linked miR-378a to several fibrosis diseases. Here, we discovered that miR-378a-3p effectively inhibited the proliferative, migratory, and COL1A1 expression effects induced by TGF-β1 in fibroblasts. Additionally, we found that miR-378a-3p exerts its anti-fibrotic properties by directly binding to FSTL1, a downstream factor involved in TGF-β1 activation. We have also demonstrated that long non-coding RNA (lncRNA) NORAD functions as a competing endogenous RNA (ceRNA) for miR-378a-3p, thereby activating the expression of FTSL1. Additionally, miR-378a-3p can be encapsulated within exosomes derived from keratinocytes and transferred to fibroblasts, resulting in an antagonistic effect against TGF-β1. The subcutaneous injection of miR-378a-3p-overexpressing keratinocytes-derived exosomes significantly attenuated skin fibrosis induced by bleomycin (BLM), as evidenced by reduced dermal thickening and decreased expression of COL1A1. Consequently, exosome-mediated delivery of miR-378a-3p holds promise as a potential therapeutic strategy for the treatment of skin fibrosis.