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

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.

Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling

“…Abnormal GSK3β signaling was recently implicated in various vascular-and fibro-proliferative diseases [35][36][37]. Previous reports [38,39] showed that total and p-GSK3β remains increased and inactivated in MCT-induced PH lung tissue and MCT-PASMCs than in control, activation of GSK3β could reduction p-GSK3β levels and related with excessive proliferation of PASMCs in PH.…”

Obesity and COVID-19: Molecular Mechanisms Linking Both Pandemics

“…In support of this notion, bleomycin-induced fibrosis is also associated with loss of resident lung MSCs [94]. In addition, Wnt/β-catenin signaling has been suggested to be an essential mechanism underlying the regulation of myofibroblast differentiation of lung-resident MSCs participated in the development of pulmonary fibrosis [95]. Thus, COVID-19 patients with obesity may suffer a more severe lung injury with pulmonary fibrosis owing to loss or dysfunctional lung resident MSCs induced by obesity.…”

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…ROS are key regulators in TGF-β-mediated fibroblast-to-myofibroblast transition which release cytokines, growth factors and ECM remodeling factors and increases tumor invasiveness (168). Targeting Wnt/β-catenin can also impair TGF-β-induced myofibroblast transition, again linking these two signaling pathways and their role in promoting metastasis through modulating the tumor microenvironment (169). High levels of hepcidin are often observed in tumors to maintain an iron-utilization phenotype within tumor cells.…”