Yuasa Hideto, Matsubara Tsutomu, Urushima Hayato, Daikoku Atsuko, Ikenaga Hiroko, Kadono Chiho, Kinoshita Masahiko, Kimura Kenjiro, Ishizawa Takeaki, Ohta Keisuke, Kawada Norifumi, Ikeda Kazuo
Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
Research Institute for Light-induced Acceleration System, Osaka Metropolitan University, Sakai, Japan.
Am J Physiol Cell Physiol. 2025 Mar 1;328(3):C757-C775. doi: 10.1152/ajpcell.00987.2024. Epub 2025 Jan 27.
The activation of hepatic stellate cells (HSCs) from a quiescent state is a cause of liver fibrosis and a therapeutic target. HSCs are resident mesenchymal cells located in the space of Disse, exhibiting specialized morphological characteristics such as a stellate shape, large lipid droplets, and direct adhesions to hepatocytes via microprojections called HSC spines. Morphological alterations in HSCs play a crucial role in initiating their activation. However, the mechanisms regulating these changes remain unexplored. In this study, we analyzed the morphological alterations associated with HSC activation in vivo using carbon tetrachloride treatment and identified the key factors regulating these changes in vitro. Following carbon tetrachloride treatment, HSCs exhibited shortened cell processes and HSC spines, adopting an oval shape. Subsequently, the HSCs underwent further morphological changes into two activated forms: flattened and complex shapes. In vitro, activation of cell division cycle 42 (Cdc42) maintained the morphological characteristics of quiescent HSCs. Cdc42 activation in HSC cell lines inhibited the expression of markers associated with activated HSCs. Cdc42 inhibitor treatment in vivo prevented quiescent HSCs from maintaining their morphological characteristics and hindered activated HSCs from reverting to the quiescent state. In addition, HSCs around fibrotic areas in the human liver exhibited morphological alterations indicative of early activation. These findings demonstrate that Cdc42 is a crucial regulator of morphological and molecular alterations associated with HSC activation, identifying it as a novel target for the development of therapeutic agents against liver fibrosis. The activation of hepatic stellate cells from a quiescent state is a cause and a therapeutic target for liver fibrosis. Morphological alterations in the hepatic stellate cells play a critical role in initiating their activation. However, the mechanisms that regulate these alterations remain unexplored. Our results indicate that cell division cycle 42 is a crucial regulator of hepatic stellate cell activation and a novel target for the development of therapeutic agents against liver fibrosis.
肝星状细胞（HSCs）从静止状态的激活是肝纤维化的一个原因及治疗靶点。肝星状细胞是位于狄氏间隙的驻留间充质细胞，具有特殊的形态学特征，如星状外形、大脂滴以及通过称为肝星状细胞棘的微突起与肝细胞直接黏附。肝星状细胞的形态改变在启动其激活过程中起关键作用。然而，调节这些变化的机制仍未被探索。在本研究中，我们使用四氯化碳处理分析了体内与肝星状细胞激活相关的形态改变，并在体外确定了调节这些变化的关键因素。四氯化碳处理后，肝星状细胞表现出细胞突起和肝星状细胞棘缩短，呈椭圆形。随后，肝星状细胞经历进一步的形态变化，转变为两种激活形式：扁平形和复杂形。在体外，细胞分裂周期42（Cdc42）的激活维持了静止肝星状细胞的形态特征。肝星状细胞系中Cdc42的激活抑制了与激活的肝星状细胞相关标志物的表达。体内Cdc42抑制剂处理阻止了静止肝星状细胞维持其形态特征，并阻碍激活的肝星状细胞恢复到静止状态。此外，人肝纤维化区域周围的肝星状细胞表现出指示早期激活的形态改变。这些发现表明，Cdc42是与肝星状细胞激活相关的形态和分子改变的关键调节因子，将其确定为开发抗肝纤维化治疗药物的新靶点。肝星状细胞从静止状态的激活是肝纤维化的一个原因及治疗靶点。肝星状细胞的形态改变在启动其激活过程中起关键作用。然而，调节这些改变的机制仍未被探索。我们的结果表明，细胞分裂周期42是肝星状细胞激活的关键调节因子，也是开发抗肝纤维化治疗药物的新靶点。
