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

Weiguo Fan¹, Tianhui Liu², Wen Chen³, Seddik Hammad⁴, Thomas Longerich⁵, Ingrid Hausser⁵, Yadong Fu⁶, Nan Li⁷, Yajing He⁸, Cui Liu⁹, Yaguang Zhang⁹, Qiaoshi Lian⁹, Xinhao Zhao⁹, Chenghua Yan⁹, Li Li¹⁰, Chunyan Yi⁹, Zhiyang Ling⁹, Liyan Ma⁹, Xinyan Zhao², Hufeng Xu², Ping Wang², Min Cong², Hong You², Zhihong Liu⁸, Yan Wang⁸, Jianfeng Chen⁹, Dangsheng Li⁹, Lijian Hui⁹, Steven Dooley¹¹, Jinlin Hou¹², Jidong Jia¹³, Bing Sun¹⁴

Affiliations

¹ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
² Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.
³ CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
⁴ Sektion Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Germany; Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
⁵ Sektion Translational Gastrointestinal Pathology, Institute of Pathology, Heidelberg University, Heidelberg, Germany.
⁶ Institute of Shanghai Municipal Education Commission Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁷ School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
⁸ Department of Infectious Diseases, Institute of Hepatology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁹ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
¹⁰ CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
¹¹ Sektion Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Germany. Electronic address: Steven.Dooley@medma.uni-heidelberg.de.
¹² Department of Infectious Diseases, Institute of Hepatology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: jlhousmu@163.com.
¹³ Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China. Electronic address: jia_jd@ccmu.edu.cn.
¹⁴ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China. Electronic address: bsun@sibs.ac.cn.

PMID: 31362006
DOI: 10.1053/j.gastro.2019.07.036

Free article

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

Weiguo Fan et al. Gastroenterology. 2019 Nov.

Free article

. 2019 Nov;157(5):1352-1367.e13.

doi: 10.1053/j.gastro.2019.07.036. Epub 2019 Jul 27.

Authors

Affiliations

¹ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
² Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China.
³ CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
⁴ Sektion Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Germany; Department of Forensic Medicine and Veterinary Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
⁵ Sektion Translational Gastrointestinal Pathology, Institute of Pathology, Heidelberg University, Heidelberg, Germany.
⁶ Institute of Shanghai Municipal Education Commission Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁷ School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
⁸ Department of Infectious Diseases, Institute of Hepatology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁹ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
¹⁰ CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Shanghai, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
¹¹ Sektion Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Germany. Electronic address: Steven.Dooley@medma.uni-heidelberg.de.
¹² Department of Infectious Diseases, Institute of Hepatology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China. Electronic address: jlhousmu@163.com.
¹³ Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China. Electronic address: jia_jd@ccmu.edu.cn.
¹⁴ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; School of Life Science and Technology, Shanghai Tech University, Shanghai, China. Electronic address: bsun@sibs.ac.cn.

PMID: 31362006
DOI: 10.1053/j.gastro.2019.07.036

Abstract

Background & aims: Activation of TGFB (transforming growth factor β) 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^Δhep). 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 αv 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 ECM1^Δhep 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.

Keywords: Cirrhosis; ECM; Integrin Signaling; Mouse Model.

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

Affiliations

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

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Abstract

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