The hedgehog and Wnt/\u03b2-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis

Xiang Chen,Chaowen Shi,Kebin Hu,Ling Chen,Xiaodong Han,Zou Xiang,Honghui Cao,Jiwei Hou

doi:10.1038/s41419-018-0692-9

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal lung disease that is characterized by enhanced changes in stem cell differentiation and fibroblast proliferation. Resident mesenchymal stem cells (LR-MSCs) can undergo phenotype conversion to myofibroblasts to augment extracellular matrix production, impairing function and contributing to pulmonary fibrosis. Hedgehog and Wnt signaling are developmental signal cascades that play an essential role in regulating embryogenesis and tissue homeostasis. Recently, it has been reported that both hedgehog and Wnt signaling play important roles in pulmonary fibrogenesis. Thus, the identification of specific target regulators may yield new strategy for pulmonary fibrosis therapies. In our work, we demonstrated the critical role of Gli1, Wnt7b, Wnt10a and Fzd10 in the process of pulmonary fibrogenesis in vitro and in vivo. Gli1 was induced in LR-MSCs following TGF-β1 treatment and fibrotic lung tissues. Inhibition of Gli1 suppressed myofibroblast differentiation of LR-MSCs and pulmonary fibrosis, and decreased the expression of Wnt7b, Wnt10a and β-catenin. Gli1 bound to and increased promoter activity of the Wnt7b and Wnt10a genes, and Wnt7b and Wnt10a were critical activators of Wnt/β-catenin signaling. It was noteworthy that Fzd10 knockdown reduced Wnt7b and Wnt10a-induced activation of Wnt/β-catenin signaling, which imply that Wnt7b and Wnt10a may be the ligands for Fzd10. Moreover, siRNA-mediated inhibition of Fzd10 prevented TGF-β1-induced myofibroblast differentiation of LR-MSCs in vitro and impaired bleomycin-induced pulmonary fibrosis. We conclude that hedgehog and Wnt/β-catenin signaling play a critical role in promoting myofibroblast differentiation of LR-MSCs and development of pulmonary fibrosis. These findings elucidate a therapeutic approach to attenuate pulmonary fibrosis through targeted inhibition of Gli1 or Fzd10.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and lethal disease of uncertain etiology[1]
LR-mesenchymal stem cells (MSCs) could differentiate into myofibroblasts in vivo The primary Lung-resident mesenchymal stem cells (LR-MSCs) from mouse lung tissues were isolated by Magnetic-activated cell sorting (MACS) as previously reported
In order to determine whether Wnt7b/10a is responsible for the differentiation of LR-MSCs, or a consequence of fibrosis, we examined the messenger RNA (mRNA) levels of α-smooth muscle actin (α-SMA) and Axin[2] in LR-MSCs which were transfected with LV-Wnt7b or LV-Wnt10a

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and lethal disease of uncertain etiology[1]. It has been reported that IPF may be a result of the migration, proliferation and activation of mesenchymal cells provoked by the aberrant activation of alveolar epithelial cells after injury. In this process, the activated mesenchymal cells would lead to the formation of fibroblastic/myofibroblastic foci and exaggerated accumulation of extracellular matrix (ECM), resulting in irreversible destruction of the lung parenchyma[2,3,4]. The Wnt/β-catenin signaling pathway was found dysregulated in the lung tissues from patients with IPF7,8. Wnt/β-catenin signaling has a profound effect on developmental processes during embryogenesis and plays a key Official journal of the Cell Death Differentiation Association

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