Lin Chen1, Jie Li1, Jinhua Zhang2, Chengliang Dai1, Xiaoman Liu2, Jun Wang3, Zhitao Gao4, Hongyan Guo5, Rui Wang5, Shichun Lu5, Fusheng Wang6, Henghui Zhang7, Hongsong Chen7, Xiaolong Fan8, Shengdian Wang9, Zhihai Qin10. 1. Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China. 2. Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. 3. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. 4. Xinxiang Medical University, Xinxiang, China. 5. Beijing YouAn Hospital, Capital Medical University, Beijing, China. 6. Department of Infectious Diseases, Beijing 302 Hospital, Beijing, China. 7. Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China. 8. Beijing Key Laboratory of Gene Resource and Molecular Development, Laboratory of Neuroscience and Brain Development, Beijing Normal University, Beijing, China. 9. Key Laboratory for Infection and Immunity, Center for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. 10. Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China; Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. Electronic address: zhihai@ibp.ac.cn.
Abstract
BACKGROUND & AIMS: S100A4 has been linked to the fibrosis of several organs due to its role as a fibroblast-specific marker. However, the role of S100A4 itself in the development of fibrosis has not been much investigated. Here, we determined whether S100A4 regulates liver fibrogenesis and examined its mechanism by focusing on the activation of hepatic stellate cells (HSCs). METHODS: S100A4 deficient mice were used to determine the role of S100A4 in liver fibrogenesis. The effect of S100A4 on HSC activation was estimated by using primary mouse HSCs and the human HSC cell line LX-2. Serum levels of S100A4 in cirrhotic patients were determined by ELISA. RESULTS: S100A4 was found to be secreted by a subpopulation of macrophages and to promote the development of liver fibrosis. It accumulated in the liver during the progression of liver fibrosis and activated HSCs in mice. In vitro studies demonstrated that S100A4 induced the overexpression of alpha-smooth muscle actin through c-Myb in HSCs. Both, the selective depletion of S100A4-expressing cells and knockdown of S100A4 in the liver by RNA interference, resulted in a reduction of liver fibrosis following injury. Importantly, increased S100A4 levels in both the liver tissue and serum correlated positively with liver fibrosis in humans. CONCLUSIONS: S100A4 promotes liver fibrosis by activating HSCs, which may represent a potential target for anti-fibrotic therapies.
BACKGROUND & AIMS:S100A4 has been linked to the fibrosis of several organs due to its role as a fibroblast-specific marker. However, the role of S100A4 itself in the development of fibrosis has not been much investigated. Here, we determined whether S100A4 regulates liver fibrogenesis and examined its mechanism by focusing on the activation of hepatic stellate cells (HSCs). METHODS:S100A4 deficient mice were used to determine the role of S100A4 in liver fibrogenesis. The effect of S100A4 on HSC activation was estimated by using primary mouse HSCs and the human HSC cell line LX-2. Serum levels of S100A4 in cirrhotic patients were determined by ELISA. RESULTS:S100A4 was found to be secreted by a subpopulation of macrophages and to promote the development of liver fibrosis. It accumulated in the liver during the progression of liver fibrosis and activated HSCs in mice. In vitro studies demonstrated that S100A4 induced the overexpression of alpha-smooth muscle actin through c-Myb in HSCs. Both, the selective depletion of S100A4-expressing cells and knockdown of S100A4 in the liver by RNA interference, resulted in a reduction of liver fibrosis following injury. Importantly, increased S100A4 levels in both the liver tissue and serum correlated positively with liver fibrosis in humans. CONCLUSIONS:S100A4 promotes liver fibrosis by activating HSCs, which may represent a potential target for anti-fibrotic therapies.