Steven Dooley

About Steven Dooley:

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SEEK ID: https://seek.lisym.org/people/38

Location: Germany

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Project positions

Other Projects: Chronic Liver Disease Progression (LiSyM-DP - Pillar II) (Molecular Hepatology - Dept of Medicine II - Medical Faculty Mannheim - Heidelberg University) ; Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF - Pillar III) (Molecular Hepatology - Dept of Medicine II - Medical Faculty Mannheim - Heidelberg University) ; LiSyM network (Molecular Hepatology - Dept of Medicine II - Medical Faculty Mannheim - Heidelberg University)

The incidence of this life-threatening acute-on-chronic liver failure (ACLF) is increasing, and early detection and cure are urgent clinical needs. Pillar III applies a Systems Medicine approach to identify the critical mechanisms of acute-on-chronic liver failure (ACLF) and to foster liver regeneration and repair.

Public web page: Not specified

Organisms: Not specified

Chronic Liver Disease Progression (LiSyM-DP - Pillar II)

Chronic liver diseases (CLD) progression leads to cirrhosis, often cancer, and ultimately to organ failure and death. Because of the complexity of this scenario, a Systems Medicine approach is chosen to develop strategies to better characterize progression and resolution of fibrosis. Pillar II aims to define key molecular mechanisms and structural changes in tissue architecture during the progression of CLD by visualizing and quantifying at a cellular level, tissue and organ scale.

Public web page: Not specified

Organisms: Mus musculus, Rattus rattus, Rattus norvegicus

LiSyM network

This comprises the whole LiSyM network

Public web page: http://www.lisym.org

Organisms: Rattus norvegicus, Rattus rattus, Mus musculus, Homo sapiens

Molecular Hepatology - Dept of Medicine II - Medical Faculty Mannheim - Heidelberg University

Country: Germany

City: 68167 Mannheim

Web page: https://w2.umm.de/3413/

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

Chronic Liver Disease Progression (LiSyM-DP - Pillar II), LiSyM network

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Abstract (Expand)

BACKGROUND & AIMS: Activation of transforming growth factor beta (TGFB) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanism of TGFB activation are not clear. We … investigated the role of extracellular matrix protein 1 (ECM1), which interacts with extracellular and structural proteins, in TGFB activation in livers of mice. METHODS: We performed studies with e C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Deltahep). ECM1 or soluble TGFB receptor 2 (TGFBR2) were expressed in livers of mice following 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 liver 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 alphav 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 ECM1Deltahep 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.

Authors: W. Fan, T. Liu, W. Chen, Seddik Hammad, T. Longerich, Y. Fu, N. Li, Y. He, C. Liu, Y. Zhang, Q. Lian, Jieling Zhao, C. Yan, L. Li, C. Yi, Z. Ling, L. Ma, Jieling Zhao, H. Xu, P. Wang, M. Cong, H. You, Z. Liu, Y. Wang, J. Chen, D. Li, L. Hui, Steven Dooley, J. Hou, J. Jia, B. Sun

Date Published: 27th Jul 2019

Journal: Gastroenterology

PubMed ID: 31362006

Citation: Gastroenterology. 2019 Jul 27. pii: S0016-5085(19)41133-5. doi: 10.1053/j.gastro.2019.07.036.

Created: 6th Aug 2019 at 07:37

Maintenance of functional hepatocellular polarity determines recovery in acute-on-chronic liver failure

Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF - Pillar III)