Cargando…

Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis

An emerging paradigm proposes a crucial role for lung resident mesenchymal stem cells (LR-MSCs) via a fibroblastic transdifferentiation event in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Aberrant activation of Wnt/β-catenin signaling occurs in virtually all fibrotic lung diseases and...

Descripción completa

Detalles Bibliográficos
Autores principales: Cao, Honghui, Wang, Cong, Chen, Xiang, Hou, Jiwei, Xiang, Zou, Shen, Yi, Han, Xiaodong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134002/
https://www.ncbi.nlm.nih.gov/pubmed/30206265
http://dx.doi.org/10.1038/s41598-018-28968-9
_version_ 1783354591159517184
author Cao, Honghui
Wang, Cong
Chen, Xiang
Hou, Jiwei
Xiang, Zou
Shen, Yi
Han, Xiaodong
author_facet Cao, Honghui
Wang, Cong
Chen, Xiang
Hou, Jiwei
Xiang, Zou
Shen, Yi
Han, Xiaodong
author_sort Cao, Honghui
collection PubMed
description An emerging paradigm proposes a crucial role for lung resident mesenchymal stem cells (LR-MSCs) via a fibroblastic transdifferentiation event in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Aberrant activation of Wnt/β-catenin signaling occurs in virtually all fibrotic lung diseases and is relevant to the differentiation of mesenchymal stem cells (MSCs). In vitro, by measuring the protein levels of several key components involved in Wnt/β-catenin signaling, we confirmed that this signaling pathway was activated in the myofibroblast differentiation of LR-MSCs. Targeted inhibition of Wnt/β-catenin signaling by a small molecule, ICG-001, dose-dependently impeded the proliferation and transforming growth factor-β1 (TGF-β1)-mediated fibrogenic actions of LR-MSCs. In vivo, ICG-001 exerted its lung protective effects after bleomycin treatment through blocking mesenchymal-myofibroblast transition, repressing matrix gene expression, and reducing cell apoptosis. Moreover, delayed administration of ICG-001 attenuated bleomycin-induced lung fibrosis, which may present a promising therapeutic strategy for intervention of IPF. Interestingly, these antifibrotic actions of ICG-001 are operated by a mechanism independent of any disruption of Smad activation. In conclusion, our study demonstrated that Wnt/β-catenin signaling may be an essential mechanism underlying the regulation of myofibroblast differentiation of LR-MSCs and their further participation in the development of pulmonary fibrosis.
format Online
Article
Text
id pubmed-6134002
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-61340022018-09-15 Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis Cao, Honghui Wang, Cong Chen, Xiang Hou, Jiwei Xiang, Zou Shen, Yi Han, Xiaodong Sci Rep Article An emerging paradigm proposes a crucial role for lung resident mesenchymal stem cells (LR-MSCs) via a fibroblastic transdifferentiation event in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Aberrant activation of Wnt/β-catenin signaling occurs in virtually all fibrotic lung diseases and is relevant to the differentiation of mesenchymal stem cells (MSCs). In vitro, by measuring the protein levels of several key components involved in Wnt/β-catenin signaling, we confirmed that this signaling pathway was activated in the myofibroblast differentiation of LR-MSCs. Targeted inhibition of Wnt/β-catenin signaling by a small molecule, ICG-001, dose-dependently impeded the proliferation and transforming growth factor-β1 (TGF-β1)-mediated fibrogenic actions of LR-MSCs. In vivo, ICG-001 exerted its lung protective effects after bleomycin treatment through blocking mesenchymal-myofibroblast transition, repressing matrix gene expression, and reducing cell apoptosis. Moreover, delayed administration of ICG-001 attenuated bleomycin-induced lung fibrosis, which may present a promising therapeutic strategy for intervention of IPF. Interestingly, these antifibrotic actions of ICG-001 are operated by a mechanism independent of any disruption of Smad activation. In conclusion, our study demonstrated that Wnt/β-catenin signaling may be an essential mechanism underlying the regulation of myofibroblast differentiation of LR-MSCs and their further participation in the development of pulmonary fibrosis. Nature Publishing Group UK 2018-09-11 /pmc/articles/PMC6134002/ /pubmed/30206265 http://dx.doi.org/10.1038/s41598-018-28968-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Cao, Honghui
Wang, Cong
Chen, Xiang
Hou, Jiwei
Xiang, Zou
Shen, Yi
Han, Xiaodong
Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
title Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
title_full Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
title_fullStr Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
title_full_unstemmed Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
title_short Inhibition of Wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
title_sort inhibition of wnt/β-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134002/
https://www.ncbi.nlm.nih.gov/pubmed/30206265
http://dx.doi.org/10.1038/s41598-018-28968-9
work_keys_str_mv AT caohonghui inhibitionofwntbcateninsignalingsuppressesmyofibroblastdifferentiationoflungresidentmesenchymalstemcellsandpulmonaryfibrosis
AT wangcong inhibitionofwntbcateninsignalingsuppressesmyofibroblastdifferentiationoflungresidentmesenchymalstemcellsandpulmonaryfibrosis
AT chenxiang inhibitionofwntbcateninsignalingsuppressesmyofibroblastdifferentiationoflungresidentmesenchymalstemcellsandpulmonaryfibrosis
AT houjiwei inhibitionofwntbcateninsignalingsuppressesmyofibroblastdifferentiationoflungresidentmesenchymalstemcellsandpulmonaryfibrosis
AT xiangzou inhibitionofwntbcateninsignalingsuppressesmyofibroblastdifferentiationoflungresidentmesenchymalstemcellsandpulmonaryfibrosis
AT shenyi inhibitionofwntbcateninsignalingsuppressesmyofibroblastdifferentiationoflungresidentmesenchymalstemcellsandpulmonaryfibrosis
AT hanxiaodong inhibitionofwntbcateninsignalingsuppressesmyofibroblastdifferentiationoflungresidentmesenchymalstemcellsandpulmonaryfibrosis