Membrane tension mediated mechanotransduction drives fate choice in embryonic stem cells

Changes in cell shape and mechanics frequently accompany cell fate transitions. Yet how mechanics affects the regulatory path- ways controlling cell fate is poorly understood. To probe the interplay between shape, mechanics and fate, we used embryonic stem (ES) cells, which spread as they undergo early differentiation. We found that this spreading is regulated by a beta-catenin mediated decrease in plasma membrane tension. Strikingly, preventing the membrane tension decrease obstructs early differentiation of ES cells. We further find that blocking the decrease in membrane tension inhibits endocytosis of FGF signalling components, which direct the exit from the ES cell state. The early differentiation defects we observed can be rescued by increasing Rab5a-facilitated endocytosis. Thus, we show that a mechanically-triggered increase in endocytosis regulates fate transitions. Our findings are of fundamental importance for understanding how cell mechanics regulates biochemical signaling, and therefore cell fate.