Exosomal miR-107 antagonizes profibrotic phenotypes of pericytes by targeting a pathway involving HIF-1α/Notch1/PDGFRβ/YAP1/Twist1 axis in vitro

Abstract

Background: Microvascular pericytes have been demonstrated as an origin for myofibroblasts that produce excessive extracellular matrix (ECM) proteins such as α-smooth muscle actin (α-SMA) and type I collagen (ColI), and contribute to pulmonary fibrosis (PF). However, the signaling mechanism responsible for ECM production within pericytes is poorly understood. In this study, we examined exosomal miR-107 in the fibrotic phenotypes of pericytes and pathogenesis of PF. Methods: MiR-107 level was compared between clinical or bleomycin-induced PF and normal pulmonary tissues using RT-qPCR. Exosomes were isolated from cultured microvascular endothelial cells (ECs) derived from normal or PF tissues, characterized using dynamic light scattering, transmission electron microscopy, flow cytometry, Western blot, and immunofluorescence, and then applied to pericytes. The effects of exosomes or different fibrosis-related signaling molecules were examined by Western blot and the potential regulations between the signaling molecules were identified using bioinformatic analysis and assessed by EMSA, ChIP, luciferase assay, and RIP. Results: MiR-107 was down-regulated in clinical or experimental PF tissues and also in exosomes from PF-derived ECs. EC-derived exosomal miR-107 essentially controlled miR-107 level and inhibited α-SMA and ColIA1 expression in pericytes. The anti-fibrosis effect of miR-107 was mediated through the suppression of HIF-1α/Notch1/PDGFRβ/YAP1/Twist1 pathway, where miR-107 directly targeted HIF-1α mRNA, while the latter directly activated the transcriptions of both Notch1 and PDGFRβ. Functionally, targeting miR-107 promoted, while targeting HIF-1α abolished the fibrotic phenotypes of pericytes. Conclusions: Exosomal miR-107 produced by pulmonary vascular ECs may alleviate pericyte-induced fibrosis by inhibiting a signaling pathway involving HIF-1α/Notch1/PDGFRβ/YAP1/Twist1.

Blockade of Exosome Release Suppresses Atrial Fibrillation by Alleviating Atrial Fibrosis in Canines With Prolonged Atrial Pacing

“…Moreover, the function of exosomes depends strongly on stimulation conditions and microenvironments-for example, Działo et al found that Wnt5a-enriched exosomes activated the ERK1/2 and JNK pathways, induced the production of IL-6, and promoted fibrosis (23). Wang et al showed that miR-107 in vascular endothelial cell-derived exosomes could alleviate fibrosis through the HIF-1α/Notch1/PDGFRβ/YAP1/Twist1 pathway (24). Thus, we investigated the impact of exosomes on atrial fibrosis in a canine model of AF.…”

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

“…Exosomes from pulmonary microvascular endothelial cells contained miR-107, which inhibited hypoxia inducible factor-1α ( HIF-1α ) in pericytes, resulting in suppression of a Notch1/PDGFRβ/yes associated protein 1 (YAP1)/Twist1 axis and downstream inhibition of αSMA and collagen 1α1 expression [ 78 ]. During pulmonary fibrosis, endothelial cell EV miR-107 levels were downregulated, resulting in enhanced HIF-1α expression and stimulation of pericyte transdifferentiation and fibrogenesis [ 78 ].…”

Current and prospective applications of exosomal microRNAs in pulmonary fibrosis (Review)

“…Thus, the overexpression of miR-627 reduces TGF-1-induced changes in NHLFs and significantly reverses the excessive EMC deposition caused by overexpression of miR155HG. Microvascular pericytes are the source of excess ECM protein produced by myofibroblasts, contributing to PF ( 90 ). miR-107 expression has been shown to be reduced in clinical or experimental mouse PF tissue samples and exosomes by PF-derived microvascular endothelial cells ( 90 ).…”

“…Microvascular pericytes are the source of excess ECM protein produced by myofibroblasts, contributing to PF ( 90 ). miR-107 expression has been shown to be reduced in clinical or experimental mouse PF tissue samples and exosomes by PF-derived microvascular endothelial cells ( 90 ). The anti-fibrotic effect of miR-107 is mediated by the inhibition of the hypoxia inducible factor 1 α (HIF-1α)/Notch1/platelet-derived growth factor receptor β (PDGFRβ)/Yes 1-associated transcriptional regulator/Twist1 signaling pathway.…”