ECM1 Prevents Activation of Transforming Growth Factor beta, Hepatic Stellate Cells, and Fibrogenesis in Mice
Fan, Weiguo1,2,3,4; Liu, Tianhui5,6,7; Chen, Wen3,4; Hammad, Seddik8,9; Longerich, Thomas10; Hausser, Ingrid10; Fu, Yadong11; Li, Nan12; He, Yajing13; Liu, Cui1,2; Zhang, Yaguang1,2; Lian, Qiaoshi1,2; Zhao, Xinhao1,2; Yan, Chenghua1,2; Li, Li3,4,12; Yi, Chunyan1,2; Ling, Zhiyang1,2; Ma, Liyan1,2; Zhao, Xinyan5,6,7; Xu, Hufeng5,6,7; Wang, Ping5,6,7; Cong, Min5,6,7; You, Hong5,6,7; Liu, Zhihong13; Wang, Yan13; Chen, Jianfeng1,2; Li, Dangsheng1,2; Hui, Lijian1,2; Dooley, Steven8; Hou, Jinlin13; Jia, Jidong5,6,7; Sun, Bing1,2,12
AbstractBACKGROUND & AIMS: Activation of TGFB (transforming growth factor beta) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanisms of TGFB activation are not clear. We investigated the role of ECM1 (extracellular matrix protein 1), which interacts with extracellular and structural proteins, in TGFB activation in mouse livers. METHODS: We performed studies with C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte- specific knockout of EMC1 (ECM1(Delta hep)). ECM1 or soluble TGFBR2 (TGFB receptor 2) were expressed in livers of mice after injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy livers were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with av integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4- induced liver fibrosis was accelerated in ECM1Dhep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.
KeywordCirrhosis Mouse Model ECM Integrin Signaling
Indexed BySCI
Funding ProjectNational Natural Science Foundation of China[81770596] ; National Natural Science Foundation of China[81641022]
WOS Research AreaGastroenterology & Hepatology
WOS SubjectGastroenterology & Hepatology
WOS IDWOS:000492148900032
Original Document TypeArticle
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Cited Times:3[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Corresponding AuthorDooley, Steven; Hou, Jinlin; Jia, Jidong; Sun, Bing
Affiliation1.Chinese Acad Sci, State Key Lab Cell Biol, CAS Ctr Excellence Mol Cell Sci, Shanghai Inst Biochem & Cell Biol, Shanghai, Peoples R China
2.Univ Chinese Acad Sci, Shanghai, Peoples R China
3.Inst Pasteur Shanghai, CAS Key Lab Mol Virol & Immunol, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai, Peoples R China
5.Capital Med Univ, Beijing Friendship Hosp, Liver Res Ctr, 95 Yong An Rd, Beijing 100050, Peoples R China
6.Beijing Key Lab Translat Med Liver Cirrhosis, Beijing, Peoples R China
7.Natl Clin Res Ctr Digest Dis, Beijing, Peoples R China
8.Heidelberg Univ, Med Fac Mannheim, Dept Med 2, Sekt Mol Hepatol, Heidelberg, Germany
9.South Valley Univ, Dept Forens Med & Vet Toxicol, Fac Vet Med, Qena, Egypt
10.Heidelberg Univ, Inst Pathol, Sekt Translat Gastrointestinal Pathol, Heidelberg, Germany
11.Shanghai Univ Tradit Chinese Med, Inst Shanghai Municipal Educ Commiss, Shanghai, Peoples R China
12.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
13.Southern Med Univ, Inst Hepatol, Nanfang Hosp, State Key Lab Organ Failure Res,Dept Infect Dis, Guangzhou, Guangdong, Peoples R China
Corresponding Author AffilicationSchool of Life Science and Technology
Recommended Citation
GB/T 7714
Fan, Weiguo,Liu, Tianhui,Chen, Wen,et al. ECM1 Prevents Activation of Transforming Growth Factor beta, Hepatic Stellate Cells, and Fibrogenesis in Mice[J]. GASTROENTEROLOGY,2019,157(5):1352-+.
APA Fan, Weiguo.,Liu, Tianhui.,Chen, Wen.,Hammad, Seddik.,Longerich, Thomas.,...&Sun, Bing.(2019).ECM1 Prevents Activation of Transforming Growth Factor beta, Hepatic Stellate Cells, and Fibrogenesis in Mice.GASTROENTEROLOGY,157(5),1352-+.
MLA Fan, Weiguo,et al."ECM1 Prevents Activation of Transforming Growth Factor beta, Hepatic Stellate Cells, and Fibrogenesis in Mice".GASTROENTEROLOGY 157.5(2019):1352-+.
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