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

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Article number692
JournalCell Death and Disease
Volume9
Issue number6
DOIs
StatePublished - Jun 1 2018

Fingerprint

Catenins
Myofibroblasts
Pulmonary Fibrosis
Lung
Idiopathic Pulmonary Fibrosis
Bleomycin
Mesenchymal Stromal Cells
Small Interfering RNA
Lung Diseases
Embryonic Development
Extracellular Matrix
Cell Differentiation
Homeostasis
Stem Cells
Fibroblasts
Ligands
Phenotype
Therapeutics
Genes

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Chen, Xiang ; Shi, Chaowen ; Cao, Honghui ; Chen, Ling ; Hou, Jiwei ; Xiang, Zou ; Hu, Kebin ; Han, Xiaodong. / The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary. In: Cell Death and Disease. 2018 ; Vol. 9, No. 6.
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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.",
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The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary. / Chen, Xiang; Shi, Chaowen; Cao, Honghui; Chen, Ling; Hou, Jiwei; Xiang, Zou; Hu, Kebin; Han, Xiaodong.

In: Cell Death and Disease, Vol. 9, No. 6, 692, 01.06.2018.

Research output: Contribution to journalArticle

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