Membrane Tension Gates ERK-Mediated Regulation of Pluripotent Cell Fate

Henry De Belly; Aki Stubb; Ayaka Yanagida; Céline Labouesse; Philip H Jones; Ewa K Paluch; Kevin J Chalut

doi:10.1016/j.stem.2020.10.018

Membrane Tension Gates ERK-Mediated Regulation of Pluripotent Cell Fate

Cell Stem Cell. 2021 Feb 4;28(2):273-284.e6. doi: 10.1016/j.stem.2020.10.018. Epub 2020 Nov 19.

Authors

Henry De Belly¹, Aki Stubb², Ayaka Yanagida³, Céline Labouesse⁴, Philip H Jones⁵, Ewa K Paluch⁶, Kevin J Chalut⁷

Affiliations

¹ 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.
² Department of Physiology, Development, and Neuroscience, Downing Street, University of Cambridge, Cambridge CB2 3DY, UK.
³ Wellcome/MRC Cambridge Stem Cell Research Institute, Puddicombe Way, University of Cambridge, Cambridge CB2 0AW, UK; Living Systems Institute, University of Exeter, Exeter EX4 4QD, UK.
⁴ Wellcome/MRC Cambridge Stem Cell Research Institute, Puddicombe Way, University of Cambridge, Cambridge CB2 0AW, UK.
⁵ Department of Physics & Astronomy, University College London, Gower Street, London WC1E 6BT, UK.
⁶ MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Department of Physiology, Development, and Neuroscience, Downing Street, University of Cambridge, Cambridge CB2 3DY, UK. Electronic address: ekp25@cam.ac.uk.
⁷ Wellcome/MRC Cambridge Stem Cell Research Institute, Puddicombe Way, University of Cambridge, Cambridge CB2 0AW, UK. Electronic address: kc370@cam.ac.uk.

Abstract

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.

Keywords: Beta-catenin; Cell fate choice; Cell surface mechanics; ERK; Embryonic stem cells; Endocytosis; Membrane tension; mechanical signalling; pluripotency.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Embryonic Stem Cells*
Endocytosis
Mice
Mouse Embryonic Stem Cells*
Signal Transduction

Abstract

Publication types

MeSH terms

Grants and funding