Inhibition of Wnt/\u03b2-catenin signaling suppresses myofibroblast differentiation of lung resident mesenchymal stem cells and pulmonary fibrosis

Honghui Cao,Xiaodong Han,Cong Wang,Jiwei Hou,Yi Shen,Xiang Chen,Zou Xiang

doi:10.1038/s41598-018-28968-9

Abstract

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.

Highlights

Idiopathic pulmonary fibrosis (IPF) is an agnogenic disease characterized by diffuse alveolar inflammation and a fibrotic lung disorder
For human lung resident mesenchymal stem cells (LR-Mesenchymal stem cells (MSCs)), cell suspensions from lung samples plated in culture medium gave rise to multiple plastic-adherent fibroblast-like cell colonies after approximately 14 days, which were expanded by subsequent trypsinization and several rounds of passaging[22]
These fibroblastic foci are revealed as accumulations of fibroblasts and myofibroblasts through epithelial-mesenchymal transition (EMT), the recruitment of circulating fibrocytes, and differentiation of resident mesenchymal cells[13,30,31]

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is an agnogenic disease characterized by diffuse alveolar inflammation and a fibrotic lung disorder. Recent evidence suggests that lung resident mesenchymal stem cells (LR-MSCs) express mRNAs encoding contractile and ECM proteins indicative of a myofibroblast progenitor cell phenotype[13] The behavior of these LR-MSCs is highly sensitive to the microenvironment to which they are exposed, and they can be driven by local factors to differentiate into myofibroblasts that contribute to lung remodeling at the expense of functional tissue repair[14]. LR-MSCs are located in the interstitial perivascular regions and exhibit the ability to differentiate into cells capable of deleterious remodeling in mouse and in human lungs[19] To date, it remains unknown whether Wnt/β-catenin signaling works on the transdifferentiation of human LR-MSCs to invasive myofibroblasts.

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Results

Conclusion