ECM1 Prevents Activation of Transforming Growth Factor beta, Hepatic Stellate Cells, and Fibrogenesis in Mice

doi:10.1053/j.gastro.2019.07.036

	ECM1 Prevents Activation of Transforming Growth Factor beta, Hepatic Stellate Cells, and Fibrogenesis in Mice
	Fan, Weiguo 1,2,3,4; Liu, Tianhui 5,6,7; Chen, Wen 3,4; Hammad, Seddik 8,9; Longerich, Thomas 10; Hausser, Ingrid 10; Fu, Yadong 11; Li, Nan12 ; He, Yajing 13; Liu, Cui 1,2; Zhang, Yaguang 1,2; Lian, Qiaoshi 1,2; Zhao, Xinhao 1,2; Yan, Chenghua 1,2; Li, Li3,4,12 ; Yi, Chunyan 1,2; Ling, Zhiyang 1,2; Ma, Liyan 1,2; Zhao, Xinyan 5,6,7; Xu, Hufeng 5,6,7; Wang, Ping 5,6,7; Cong, Min 5,6,7; You, Hong 5,6,7; Liu, Zhihong 13; Wang, Yan 13; Chen, Jianfeng 1,2; Li, Dangsheng 1,2; Hui, Lijian 1,2; Dooley, Steven 8; Hou, Jinlin 13; Jia, Jidong 5,6,7; Sun, Bing1,2,12
	2019-11
发表期刊	GASTROENTEROLOGY
ISSN	0016-5085
EISSN	1528-0012
卷号	157 期号:5 页码:1352-+
发表状态	已发表
DOI	10.1053/j.gastro.2019.07.036
摘要	BACKGROUND & 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.
关键词	Cirrhosis Mouse Model ECM Integrin Signaling
收录类别	SCI ; SCIE
语种	英语
资助项目	National Natural Science Foundation of China[81770596] ; National Natural Science Foundation of China[81641022]
WOS研究方向	Gastroenterology & Hepatology
WOS类目	Gastroenterology & Hepatology
WOS记录号	WOS:000492148900032
出版者	W B SAUNDERS CO-ELSEVIER INC
WOS关键词	EXTRACELLULAR-MATRIX PROTEIN-1 ; LIVER FIBROSIS ; MOUSE ; GENE ; BILE
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/80511
专题	生命科学与技术学院_硕士生生命科学与技术学院_PI研究组_王皞鹏组生命科学与技术学院_特聘教授组_孙兵组
通讯作者	Dooley, Steven; Hou, Jinlin; Jia, Jidong; Sun, Bing
作者单位	1.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
通讯作者单位	生命科学与技术学院
推荐引用方式 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-+.