title: Inhibition of Wnt/β-catenin signaling promotes epithelial differentiation of mesenchymal stem cells and repairs bleomycin-induced lung injury.
abstract: Idiopathic pulmonary fibrosis is a progressive lung disorder of unknown etiology. Previous studies have shown that aberrant activation of the Wnt/β-catenin signaling cascade occurs in lungs of patients with idiopathic pulmonary fibrosis. Given the important roles of the Wnt/β-catenin signaling pathway in the development of pulmonary fibrosis, we targeted this pathway for the intervention of pulmonary fibrosis with XAV939, a small molecule that specifically inhibits Tankyrase 1/2, eventually leading to the degradation of β-catenin and suppression of the Wnt/β-catenin signaling pathway. Our results demonstrated that XAV939 significantly inhibited the activation of Wnt/β-catenin signaling and attenuated bleomycin-induced lung fibrosis in mice, and thus improved the survival of mice with lung injury. Interestingly, previous investigations have confirmed that endogenous and exogenous mesenchymal stem cells could be recruited to the injured lung, although the exact effects of these cells are debatable. To determine the effect of Wnt/β-catenin signaling in the epithelial differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs), we established a coculture system that contains BM-MSCs and alveolar type II epithelial cells. The in vitro experiments demonstrated that XAV939 could promote the differentiation of BM-MSCs into an epithelium-like phenotype in the coculture system. We also found that XAV939 could inhibit the proliferation and myofibroblast differentiation of NIH/3T3 fibroblasts. This work supports that inhibition of the Wnt/β-catenin signaling pathway may be exploited for the treatment of idiopathic pulmonary fibrosis for which effective treatment strategies are still lacking.
authors.affiliation: Immunology and Reproductive Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu, China;
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Immunology and Reproductive Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu, China;
authors.forename: Huiming
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Emergency, Jinling Hospital, Medical School, Nanjing University, Nanjing, Jiangsu, China;
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden; and.
authors.forename: Zou
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Immunology and Reproductive Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu, China;
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Immunology and Reproductive Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu, China;
authors.forename: Can
authors.initials: C
authors.lastname: Ni
authors.affiliation: Immunology and Reproductive Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu, China;
authors.forename: Zhaowen
authors.initials: Z
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Bioelectronics, Southeast University, Nanjing, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Qian
authors.affiliation: Immunology and Reproductive Biology Laboratory, Medical School, Nanjing University, Nanjing, Jiangsu, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu, China; hanxd@nju.edu.cn.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Han
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000166:cytology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy / Q000473:pathology*; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D051153:Wnt Proteins; C544261:XAV939; D051176:beta Catenin; D001761:Bleomycin
keywords: Wnt/β-catenin signaling pathway; XAV939; alveolar type II epithelial cells; bone marrow-derived mesenchymal stem cells; coculture; idiopathic pulmonary fibrosis