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Exosomal microRNA-21 derived from bronchial epithelial cells is involved in aberrant epithelium-fibroblast cross-talk in COPD induced by cigarette smoking.

ABSTRACT: Rationale: Aberrant bronchial epithelium-fibroblast communication is essential for the airway remodeling that contributes to chronic obstructive pulmonary disease (COPD). Exosomes have emerged as novel mediators of intercellular communication, but their role in cigarette smoke (CS)-induced COPD is unknown. Here, we investigated the role of exosomal miR-21 in the dysfunctional epithelium-fibroblast cross-talk caused by CS. Methods: Normal or CS extract (CSE)-treated human bronchial epithelial (HBE) cells were co-cultured with bronchial fibroblasts (MRC-5 cells). Exosomes were obtained from culture media or serum by use of commercial kits. The size distribution and concentration of exosomes were analyzed by nanoparticle tracking analysis using a ZetaView particle tracker from ParticleMetrix. Inhibition of miR-21 levels by tail vein injection of antagomir-21 into mice exposed to CS was used to demonstrate the role of miR-21 in airway remodeling leading to COPD in animals. Results: For MRC-5 cells, co-culture with CSE-treated HBE cells or with exosomes derived from CSE-treated HBE cells resulted in the myofibroblast differentiation phenotype. Exosomal miR-21 was responsible for myofibroblast differentiation through hypoxia-inducible factor 1? (HIF-1?) signaling by targeting the von Hippel-Lindau protein (pVHL); HIF-1? transcriptionally regulated the ?-SMA gene. For mice, downregulation of miR-21 prevented CS-induced airway remodeling. The levels of exosomal miR-21 were high in sera of smokers and COPD patients and inversely correlated with FEV1/FVC. Conclusion: We demonstrate that CS triggers the modification of exosome components and identify miR-21 derived from bronchial epithelial cells as a mediator of myofibroblast differentiation through the pVHL/HIF-1? signaling pathway, which has potential value for diagnosis and treatment of COPD.


PROVIDER: S-EPMC6276085 | BioStudies | 2018-01-01T00:00:00Z

REPOSITORIES: biostudies

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