Cdc42对肝星状细胞活化的早期调控至关重要。

IF 5 2区 生物学 Q2 CELL BIOLOGY
Hideto Yuasa, Tsutomu Matsubara, Hayato Urushima, Atsuko Daikoku, Hiroko Ikenaga, Chiho Kadono, Masahiko Kinoshita, Kenjiro Kimura, Takeaki Ishizawa, Keisuke Ohta, Norifumi Kawada, Kazuo Ikeda
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引用次数: 0

摘要

肝星状细胞(hsc)从静止状态激活是肝纤维化的一个原因,也是一个治疗靶点。HSC是位于椎间盘间隙的常驻间充质细胞,表现出特殊的形态特征,如星状、大脂滴,并通过称为HSC棘的微突起与肝细胞直接粘附。造血干细胞的形态学改变在激活造血干细胞过程中起着至关重要的作用。然而,调节这些变化的机制仍未被探索。在这项研究中,我们分析了四氯化碳处理在体内与HSC活化相关的形态学改变,并确定了体外调节这些变化的关键因素。四氯化碳处理后,HSC细胞突起缩短,棘呈椭圆形。随后,造血干细胞进一步发生形态变化,形成扁平形状和复杂形状两种活化形式。在体外,细胞分裂周期42 (Cdc42)的激活维持了静止hsc的形态特征。Cdc42在造血干细胞中的激活抑制了与活化造血干细胞相关的标志物的表达。体内Cdc42抑制剂处理可阻止静止hsc维持其形态特征,并阻碍活化的hsc恢复到静止状态。此外,人类肝脏纤维化区域周围的造血干细胞表现出早期激活的形态学改变。这些发现表明,Cdc42是与HSC激活相关的形态学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剂的新靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cdc42 is crucial for the early regulation of hepatic stellate cell activation.

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.NEW & NOTEWORTHY 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.

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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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