Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 63, Issue 5, Pages 623-636Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2020-0002OC
Keywords
exosome; fibroblast; epithelial cell; cellular senescence; mitochondrial damage
Funding
- Center of Open Innovation Network for Smart Health initiated by the Council for Science
- Basic Science and Platform Technology Program for Innovative Biological Medicine from Japan Agency for Medical Research and Development (AMED)
- Practical Research Project for Rare Intractable Diseases from AMED
- Ministry of Health, Labor and Welfare of Japan
- GSK Japan
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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 patients with IPF induce cellular senescence via EV-mediated transfer of pathogenic cargo to lung epithelial cells. Mechanistically, IPF LF-derived EVs increased mitochondrial reactive oxygen species and associated mitochondria! 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 microRNA-23b-3p (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 microRNA-containing EVs.
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