Exosomal miR-17-5p derived from epithelial cells is involved in aberrant epithelium-fibroblast cross-talk and induces the development of oral submucosal fibrosis

Abstract Oral submucous fibrosis (OSF) is a chronic and inflammatory mucosal disease caused by betel quid chewing, which is an oral potential malignant disorder. The abnormal differentiation of fibroblasts leading to collagen metabolism disorder is the core process of OSF development. As the first line of defense against the external environment, epithelium can convert external signals into pathological signals and participate in the remodeling of fibrotic microenvironment. However, the specific mechanisms underlying epithelium drives fibroblast differentiation remains unclear. In this study, we found that arecoline exposed epithelium communicated with the fibrosis microenvironment by secreting exosomes. MiR-17-5p was enclosed in epithelial-derived exosomes and absorbed by fibroblasts, promoting cell secretion, contraction, migration and fibrogenic marker expression (α-SMA and collagen I). Underlying molecular mechanism was miR-17-5p targeting Smad7, thus promoting the degradation of the Smad7 through the ubiquitin-proteasome pathway and amplifying the classical TGF-β fibrotic pathway. Targeting miR-17-5p with its inhibitor to treat fibroblasts can restore the cell contraction and migration phenotype induced by epithelial-derived exosomes. It was confirming that exosomal miR-17-5p can act as a key regulator of phenotypic transformation of fibroblasts. In conclusion, we demonstrate that arecoline triggers aberrant epithelium-fibroblast cross-talk and identify miR-17-5p derived from epithelial cells as a mediator of fibroblast differentiation through the classical TGF-β fibrotic pathway, which provided a new perspective and strategy for diagnosis and treatment of OSF.