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.
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.
J Hepatol. 2015 Jan;62(1):156-64. doi: 10.1016/j.jhep.2014.07.035. Epub 2014 Aug 9.
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).
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.
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.
S100A4 promotes liver fibrosis by activating HSCs, which may represent a potential target for anti-fibrotic therapies.
由于 S100A4 是成纤维细胞的特异性标志物，因此它与几种器官的纤维化有关。然而，S100A4 本身在纤维化发展中的作用尚未得到广泛研究。在这里，我们通过关注肝星状细胞（HSCs）的激活，确定了 S100A4 是否调节肝纤维化，并研究了其机制。
使用 S100A4 缺陷型小鼠来确定 S100A4 在肝纤维化形成中的作用。通过使用原代小鼠 HSCs 和人 HSC 细胞系 LX-2 来评估 S100A4 对 HSC 激活的影响。通过 ELISA 测定肝硬化患者血清中 S100A4 的水平。
发现 S100A4 由巨噬细胞的一个亚群分泌，并促进肝纤维化的发展。在肝纤维化进展过程中，S100A4 在肝脏中积累并激活小鼠的 HSCs。体外研究表明，S100A4 通过 c-Myb 在 HSCs 中诱导α-平滑肌肌动蛋白的过表达。选择性耗尽 S100A4 表达细胞以及通过 RNA 干扰在肝脏中敲低 S100A4，均可减少损伤后肝纤维化的发生。重要的是，肝组织和血清中 S100A4 水平的增加与人类的肝纤维化呈正相关。
S100A4 通过激活 HSCs 促进肝纤维化，这可能代表抗纤维化治疗的潜在靶点。
