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.

细胞命运转变经常伴随着细胞形状和力学的变化。然而，细胞力学如何影响控制细胞命运的指导性信号通路却知之甚少。为了探究形状、力学和命运之间的相互作用，我们使用小鼠胚胎干细胞 (ESC)，它们在早期分化时会改变形状。我们发现形状变化受 β-连环蛋白介导的 RhoA 活性降低和随后质膜张力降低的调节。引人注目的是，防止膜张力降低会导致胚胎干细胞和原肠胚的早期分化缺陷。降低的膜张力促进 FGF 信号成分的内吞作用，从而激活 ERK 信号并指导退出 ESC 状态。增加 Rab5a 促进的内吞作用可以挽救有缺陷的早期分化。因此，我们表明内吞作用的机械触发增加调节了早期分化。我们的研究结果对于了解细胞力学如何调节生化信号传导以及细胞命运具有至关重要的意义。