Dataset Information

MiR-877-3p targets Smad7 and is associated with myofibroblast differentiation and bleomycin-induced lung fibrosis.

ABSTRACT: Myofibroblast differentiation of lung resident mesenchymal stem cells (LR-MSC) plays an important role in idiopathic pulmonary fibrosis. By comparing the expression profiles of miRNAs before and after myofibroblast differentiation of LR-MSC, we identified miR-877-3p as a fibrosis-related miRNA. We found that miR-877-3p sequestration inhibited the myofibroblast differentiation of LR-MSC and attenuates bleomycin-induced lung fibrosis by targeting Smad7. Smad7, as an inhibitory smad in the TGF-β1 signaling pathway, was decreased in the myofibroblast differentiation of LR-MSC and up-regulation of Smad7 could inhibit the differentiation process. Our data implicates a potential application of miR-877-3p as a fibrosis suppressor for pulmonary fibrosis therapy and also as a fibrosis marker for predicting prognosis.

SUBMITTER: Wang C

PROVIDER: S-EPMC4957095 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

miR-877-3p targets Smad7 and is associated with myofibroblast differentiation and bleomycin-induced lung fibrosis.

Wang Cong C Gu Shen S Cao Honghui H Li Zutong Z Xiang Zou Z Hu Kebin K Han Xiaodong X

Scientific reports 20160722

Myofibroblast differentiation of lung resident mesenchymal stem cells (LR-MSC) plays an important role in idiopathic pulmonary fibrosis. By comparing the expression profiles of miRNAs before and after myofibroblast differentiation of LR-MSC, we identified miR-877-3p as a fibrosis-related miRNA. We found that miR-877-3p sequestration inhibited the myofibroblast differentiation of LR-MSC and attenuates bleomycin-induced lung fibrosis by targeting Smad7. Smad7, as an inhibitory smad in the TGF-β1 s ...[more]

PMID: 27444321

Similar Datasets

Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive disease of insidious onset, and is responsible for up to 30,000 deaths per year in the U.S. Excessive production of extracellular matrix by myofibroblasts has been shown to be an important pathological feature in IPF. TGF-β1 is expressed in fibrotic lung and promotes fibroblast to myofibroblast differentiation (FMD) as well as matrix deposition.MethodsTo identify the mechanism of Arsenic trioxide's (ATO)'s anti-fibrotic effect in vitro, normal human lung fibroblasts (NHLFs) were treated with ATO for 24 hours and were then exposed to TGF-β1 (1 ng/ml) before harvesting at multiple time points. To investigate whether ATO is able to alleviate lung fibrosis in vivo, C57BL/6 mice were administered bleomycin by oropharyngeal aspiration and ATO was injected intraperitoneally daily for 14 days. Quantitative real-time PCR, western blotting, and immunofluorescent staining were used to assess the expression of fibrotic markers such as α-smooth muscle actin (α-SMA) and α-1 type I collagen.ResultsTreatment of NHLFs with ATO at very low concentrations (10-20nM) inhibits TGF-β1-induced α-smooth muscle actin (α-SMA) and α-1 type I collagen mRNA and protein expression. ATO also diminishes the TGF-β1-mediated contractile response in NHLFs. ATO's down-regulation of profibrotic molecules is associated with inhibition of Akt, as well as Smad2/Smad3 phosphorylation. TGF-β1-induced H2O2 and NOX-4 mRNA expression are also blocked by ATO. ATO-mediated reduction in Smad3 phosphorylation correlated with a reduction of promyelocytic leukemia (PML) nuclear bodies and PML protein expression. PML-/- mouse embryonic fibroblasts (MEFs) showed decreased fibronectin and PAI-1 expression in response to TGF-β1. Daily intraperitoneal injection of ATO (1 mg/kg) in C57BL/6 mice inhibits bleomycin induced lung α-1 type I collagen mRNA and protein expression.ConclusionsIn summary, these data indicate that low concentrations of ATO inhibit TGF-β1-induced fibroblast to myofibroblast differentiation and decreases bleomycin induced pulmonary fibrosis.

Project description:Fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of pulmonary fibrosis. Mice lacking FGF2 have increased mortality and impaired epithelial recovery after bleomycin exposure, supporting a protective or reparative function following lung injury. To determine whether FGF2 overexpression reduces bleomycin-induced injury, we developed an inducible genetic system to express FGF2 in type II pneumocytes. Double-transgenic (DTG) mice with doxycycline-inducible overexpression of human FGF2 (SPC-rtTA;TRE-hFGF2) or single-transgenic controls were administered intratracheal bleomycin and fed doxycycline chow, starting at either day 0 or day 7. In addition, wild-type mice received intratracheal or intravenous recombinant FGF2, starting at the time of bleomycin treatment. Compared to controls, doxycycline-induced DTG mice had decreased pulmonary fibrosis 21 days after bleomycin, as assessed by gene expression and histology. This beneficial effect was seen when FGF2 overexpression was induced at day 0 or day 7 after bleomycin. FGF2 overexpression did not alter epithelial gene expression, bronchoalveolar lavage cellularity or total protein. In vitro studies using primary mouse and human lung fibroblasts showed that FGF2 strongly inhibited baseline and TGFβ1-induced expression of alpha smooth muscle actin (αSMA), collagen, and connective tissue growth factor. While FGF2 did not suppress phosphorylation of Smad2 or Smad-dependent gene expression, FGF2 inhibited TGFβ1-induced stress fiber formation and serum response factor-dependent gene expression. FGF2 inhibition of stress fiber formation and αSMA requires FGF receptor 1 (FGFR1) and downstream MEK/ERK, but not AKT signaling. In summary, overexpression of FGF2 protects against bleomycin-induced pulmonary fibrosis in vivo and reverses TGFβ1-induced collagen and αSMA expression and stress fiber formation in lung fibroblasts in vitro, without affecting either inflammation or epithelial gene expression. Our results suggest that in the lung, FGF2 is antifibrotic in part through decreased collagen expression and fibroblast to myofibroblast differentiation. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Dataset Information

MiR-877-3p targets Smad7 and is associated with myofibroblast differentiation and bleomycin-induced lung fibrosis.

Publications

miR-877-3p targets Smad7 and is associated with myofibroblast differentiation and bleomycin-induced lung fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets