Wnt8b Regulates Myofibroblast Differentiation of Lung-Resident Mesenchymal Stem Cells via the Activation of Wnt/β-catenin Signaling in Pulmonary Fibrogenesis

Abstract BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease that is characterized by enhanced changes in stem cell differentiation and fibroblast proliferation. Lung resident mesenchymal stem cells (LR-MSCs) are important regulators of pathophysiological processes including tissue repair and inflammation, and evidence suggests that this cell population also plays an essential role in fibrosis. Our previous study demonstrated that Wnt/β-catenin signaling is aberrantly activated in the lungs of bleomycin-treated mice and induces myofibroblast differentiation of LR-MSCs. However, the underlying correlation between LR-MSCs and the Wnt/β-catenin signaling remains poorly understood. MethodsWe used mRNA microarray, immunohistochemistry assay, qRT-PCR, and western blotting to measure the expression of Wnt8b in myofibroblast differentiation of LR-MSCs and BLM-induced mouse fibrotic lungs. Immunofluorescence staining and western blotting were performed to analyze myofibroblast differentiation of LR-MSCs after overexpressing or silence Wnt8b. Moreover, we analyzed the effects of Wnt8b inhibition on BLM-induced pulmonary fibrosis by Sirius Red Staining and immunohistochemical staining.ResultsWe found that Wnt8b was highly expressed by LR-MSCs undergoing myofibroblast differentiation. In vitro, Wnt8b promoted LR-MSCs differentiate into myofibroblasts via activating Wnt/β-catenin signaling. Moreover, siRNA-mediated inhibition of Wnt8b prevented Transforming growth factor (TGF)-β1-induced myofibroblast differentiation of LR-MSCs in vitro and ameliorated pulmonary fibrotic lesions. ConclusionsOur study identified Wnt proteins and Wnt/β-catenin signaling in pulmonary fibrosis in vitro and in vivo, and highlighted Wnt8b as a potential therapeutic target in pulmonary fibrosis. Moreover, these finding might provide a new perspective in the development of treatment strategies for IPF.