title: Inhibition of Wnt/β-catenin signaling promotes engraftment of mesenchymal stem cells to repair lung injury.
abstract: We sought to explore the treatment effects and the repair mechanisms of bone marrow derived mesenchymal stem cells (MSCs) during HCl-induced acute lung injury (ALI). MSCs were delivered through the tail veins of rats 24 h after intranasal instillation of HCl. The results showed that MSCs did not ameliorate the histopathologic changes of ALI and pulmonary fibrosis. We found that the activated Wnt/β-catenin signaling may regulate the differentiation of MSCs and is associated with lung fibroblasts activation, pulmonary fibrosis and tissue repair process in ALI rats. Immunofluorescence and histology analysis indicated that activated canonical Wnt/β-catenin signaling induced most MSCs to differentiate into myofibroblasts or fibroblasts in vivo. However, inhibition of Wnt/β-catenin signaling by Dickkopf-1 (DKK1) promotes epithelial differentiation of MSCs induced by native alveolar epithelial cells which are beneficial to repair the injured lung epithelium. Inhibition of Wnt/β-catenin signaling after MSCs transplantation ameliorated pulmonary fibrosis and improved pulmonary function which attenuated the lung injury. In vitro study, activation of the Wnt/β-catenin signaling stimulated MSCs to express myofibroblasts markers, which was attenuated by DKK1. Furthermore, Wnt3α activated Wnt/β-catenin signaling in lung fibroblasts to enhance the expression of collagen I, vimentin and α-smooth muscle actin, but DKK1 attenuated these proteins expression. These findings demonstrated that canonical Wnt/β-catenin signaling plays a key role in regulating differentiation of MSCs in vivo or in vitro and the pathogenesis of fibrotic diseases. Our study suggested that inhibition of abnormal activated Wnt/β-catenin signaling would promote MSCs epithelial differentiation to repair lung injury and reduce pulmonary fibrosis.
authors.affiliation: Immunology and Reproductive Biology Laboratory, Medical College of Nanjing University, Nanjing, PR China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, PR China; State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, PR China.
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Sun
authors.forename: Xuemin
authors.initials: X
authors.lastname: Gong
authors.forename: Huiming
authors.initials: H
authors.lastname: Zhu
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Xu
authors.forename: Di
authors.initials: D
authors.lastname: Cui
authors.forename: Weiping
authors.initials: W
authors.lastname: Qian
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Han
mesh_terms: D000818:Animals; D004847:Epithelial Cells; D005786:Gene Expression Regulation; D006851:Hydrochloric Acid / Q000633:toxicity; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced* / Q000628:therapy*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C531384:Dkk1 protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D006851:Hydrochloric Acid