Extracellular Vesicles from Fibroblasts Induce Epithelial Cell Senescence in Pulmonary Fibrosis.

Aberrant epithelial-mesenchymal interactions have critical roles in regulating fibrosis development. The involvement of extracellular vesicles (EVs), including exosomes, remains to be elucidated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Here, we found that lung fibroblasts (LFs) from IPF patients induce cellular senescence via EV-mediated transfer of pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF-derived EVs increased mitochondrial reactive oxygen species (mtROS) and associated mitochondrial damage in lung epithelial cells, leading to activation of the DNA damage response and subsequent epithelial cell senescence. We showed that IPF LF-derived EVs contain elevated levels of miR-23b-3p and miR-494-3p, which suppress SIRT3, resulting in the epithelial EV-induced phenotypic changes. Furthermore, the levels of miR-23b-3p and miR-494-3p found in IPF LF-derived EVs correlated positively with IPF disease severity. These findings reveal that the accelerated epithelial cell mitochondrial damage and senescence observed during IPF pathogenesis are caused by a novel paracrine effect of IPF fibroblasts via miRNA-containing EVs.