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The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis.
Cell Death Dis. 2018 05 29; 9(6):639.CD

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.

Authors+Show Affiliations

Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China. Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China.Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China. Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China.Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China. Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China.Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China. Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China.Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China. Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China.Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.Department of Medicine, Division of Nephrology, Penn State University College of Medicine, Hershey, PA, 17033, USA.Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China. hanxd@nju.edu.cn. Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China. hanxd@nju.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29844390

Citation

Chen, Xiang, et al. "The Hedgehog and Wnt/β-catenin System Machinery Mediate Myofibroblast Differentiation of LR-MSCs in Pulmonary Fibrogenesis." Cell Death & Disease, vol. 9, no. 6, 2018, p. 639.
Chen X, Shi C, Cao H, et al. The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis. Cell Death Dis. 2018;9(6):639.
Chen, X., Shi, C., Cao, H., Chen, L., Hou, J., Xiang, Z., Hu, K., & Han, X. (2018). The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis. Cell Death & Disease, 9(6), 639. https://doi.org/10.1038/s41419-018-0692-9
Chen X, et al. The Hedgehog and Wnt/β-catenin System Machinery Mediate Myofibroblast Differentiation of LR-MSCs in Pulmonary Fibrogenesis. Cell Death Dis. 2018 05 29;9(6):639. PubMed PMID: 29844390.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The hedgehog and Wnt/β-catenin system machinery mediate myofibroblast differentiation of LR-MSCs in pulmonary fibrogenesis. AU - Chen,Xiang, AU - Shi,Chaowen, AU - Cao,Honghui, AU - Chen,Ling, AU - Hou,Jiwei, AU - Xiang,Zou, AU - Hu,Kebin, AU - Han,Xiaodong, Y1 - 2018/05/29/ PY - 2018/03/27/received PY - 2018/05/07/accepted PY - 2018/5/31/entrez PY - 2018/5/31/pubmed PY - 2019/12/18/medline SP - 639 EP - 639 JF - Cell death & disease JO - Cell Death Dis VL - 9 IS - 6 N2 - 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. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/29844390/The_hedgehog_and_Wnt/β_catenin_system_machinery_mediate_myofibroblast_differentiation_of_LR_MSCs_in_pulmonary_fibrogenesis_ L2 - https://doi.org/10.1038/s41419-018-0692-9 DB - PRIME DP - Unbound Medicine ER -