F-actin dynamics regulates mammalian organ growth and cell fate maintenance
F-actin dynamics regulates mammalian organ growth and cell fate maintenance
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DOI：
10.1016/j.jhep.2019.02.022
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发表时间：
2019-07-01
影响因子：
25.7
通讯作者：
Dupont, Sirio
中科院分区：
文献类型：
--
作者：
Pocaterra, Arianna;Santinon, Giulia;Dupont, Sirio
背景与目的：在体外，细胞功能可以通过细胞及其微环境的机械特性进行有效调节。细胞通过其肌动球蛋白细胞骨架产生力来测量这些特征，并相应地通过调节细胞内途径（包括转录辅激活因子雅普/TAZ）来响应。无论是机械线索是相关的成人器官内稳态的体内调节，以及是否发生这种情况，通过雅普/TAZ，仍然在很大程度上未addressed.Methods：我们开发的Capzb条件性基因敲除小鼠，并获得原代成纤维细胞的特点，在体外的作用CAPZ。通过诱导Capzb在成年肝细胞中失活、通过流体动力学尾静脉注射操纵雅普/Hippo活性以及用ROCK抑制剂法舒地尔处理小鼠来进行体内功能分析。Capzb失活改变了应力纤维和粘着斑动力学，导致肌球蛋白活性增强，牵引力增加，和肝硬化在体外，这使雅普免于受到小细胞几何结构的抑制;在体内，它诱导雅普与Hippo途径平行的激活，引起广泛的肝细胞增殖并导致显著的器官过度生长。此外，Capzb是维持分化的肝细胞状态、代谢分区和肝细胞生成所必需的。与组织力学的变化一致，抑制收缩调节因子ROCK或删除Yap 1机械转换器，逆转了Capzb缺失肝脏中出现的表型。结论：这些结果表明CAPZ在调节细胞和组织的机械性能方面具有以前未被怀疑的作用，这是肝细胞维持分化状态和调节器官大小所需的。更一般地说，它首次表明机械转导在维持哺乳动物肝脏内环境稳定方面具有生理作用。综述：细胞和组织的机械性质（即它们是软的还是硬的）被认为是细胞行为的重要调节器。在此，我们发现蛋白质CAPZ的失活改变了细胞和肝组织的机械性质，导致雅普超活化。反过来，这深刻地改变了肝脏生理学，导致器官过度生长，肝细胞分化和代谢缺陷。这些结果揭示了一个以前未表征的作用，机械信号在维持成人肝脏稳态。(C)2019年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: In vitro, cell function can be potently regulated by the mechanical properties of cells and of their microenvironment. Cells measure these features by developing forces via their actomyosin cytoskeleton, and respond accordingly by regulating intracellular pathways, including the transcriptional coactivators YAP/TAZ. Whether mechanical cues are relevant for in vivo regulation of adult organ homeostasis, and whether this occurs through YAP/TAZ, remains largely unaddressed.Methods: We developed Capzb conditional knockout mice and obtained primary fibroblasts to characterize the role of CAPZ in vitro. In vivo functional analyses were carried out by inducing Capzb inactivation in adult hepatocytes, manipulating YAP/Hippo activity by hydrodynamic tail vein injections, and treating mice with the ROCK inhibitor, fasudil.Results: We found that the F-actin capping protein CAPZ restrains actomyosin contractility: Capzb inactivation alters stress fiber and focal adhesion dynamics leading to enhanced myosin activity, increased traction forces, and increased liver stiffness. In vitro, this rescues YAP from inhibition by a small cellular geometry; in vivo, it induces YAP activation in parallel to the Hippo pathway, causing extensive hepatocyte proliferation and leading to striking organ overgrowth. Moreover, Capzb is required for the maintenance of the differentiated hepatocyte state, for metabolic zonation, and for gluconeogenesis. In keeping with changes in tissue mechanics, inhibition of the contractility regulator ROCK, or deletion of the Yap1 mechanotransducer, reverse the phenotypes emerging in Capzb-null livers.Conclusions: These results indicate a previously unsuspected role for CAPZ in tuning the mechanical properties of cells and tissues, which is required in hepatocytes for the maintenance of the differentiated state and to regulate organ size. More generally, it indicates for the first time that mechanotransduction has a physiological role in maintaining liver homeostasis in mammals.Lay summary: The mechanical properties of cells and tissues (i.e. whether they are soft or stiff) are thought to be important regulators of cell behavior. Herein, we found that inactivation of the protein CAPZ alters the mechanical properties of cells and liver tissues, leading to YAP hyperactivation. In turn, this profoundly alters liver physiology, causing organ overgrowth, defects in liver cell differentiation and metabolism. These results reveal a previously uncharacterized role for mechanical signals in the maintenance of adult liver homeostasis. (C) 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.