细胞膜张力门控 ERK 介导的多能性细胞命运调控。
Membrane Tension Gates ERK-Mediated Regulation of Pluripotent Cell Fate.
机构信息
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Wellcome/MRC Cambridge Stem Cell Research Institute, Puddicombe Way, University of Cambridge, Cambridge CB2 0AW, UK; Department of Physiology, Development, and Neuroscience, Downing Street, University of Cambridge, Cambridge CB2 3DY, UK.
Department of Physiology, Development, and Neuroscience, Downing Street, University of Cambridge, Cambridge CB2 3DY, UK.
出版信息
Cell Stem Cell. 2021 Feb 4;28(2):273-284.e6. doi: 10.1016/j.stem.2020.10.018. Epub 2020 Nov 19.
Cell fate transitions are frequently accompanied by changes in cell shape and mechanics. However, how cellular mechanics affects the instructive signaling pathways controlling cell fate is poorly understood. To probe the interplay between shape, mechanics, and fate, we use mouse embryonic stem cells (ESCs), which change shape as they undergo early differentiation. We find that shape change is regulated by a β-catenin-mediated decrease in RhoA activity and subsequent decrease in the plasma membrane tension. Strikingly, preventing a decrease in membrane tension results in early differentiation defects in ESCs and gastruloids. Decreased membrane tension facilitates the endocytosis of FGF signaling components, which activate ERK signaling and direct the exit from the ESC state. Increasing Rab5a-facilitated endocytosis rescues defective early differentiation. Thus, we show that a mechanically triggered increase in endocytosis regulates early differentiation. Our findings are of fundamental importance for understanding how cell mechanics regulates biochemical signaling and therefore cell fate.
细胞命运的转变通常伴随着细胞形状和力学性质的变化。然而，细胞力学如何影响控制细胞命运的指令性信号通路还知之甚少。为了探究形状、力学和命运之间的相互作用，我们使用了经历早期分化的小鼠胚胎干细胞（ESCs），它们的形状会发生变化。我们发现，β-catenin 介导的 RhoA 活性降低和随后的质膜张力降低调节了形状变化。引人注目的是，防止膜张力降低会导致 ESCs 和原肠胚体的早期分化缺陷。降低的膜张力促进了 FGF 信号成分的内吞作用，从而激活 ERK 信号并促使 ESC 状态退出。增加 Rab5a 促进的内吞作用可挽救分化缺陷。因此，我们表明，机械触发的内吞作用增加调节了早期分化。我们的发现对于理解细胞力学如何调节生化信号进而调节细胞命运具有重要的基础意义。
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