Membrane potential mediates an ancient mechano-transduction mechanism for multi-cellular homeostasis.

Membrane potential is a property of all living cells 1 . However, its physiological role in nonexcitable cells is poorly understood. Resting membrane potential is typically considered fixed for a given cell type and under tight homeostatic control 2 , akin to body temperature in mammals. Contrary to this widely accepted paradigm, we found that membrane potential is a dynamic property that directly reflects tissue density and mechanical forces acting on the cell. Serving as a quasi-instantaneous, global readout of density and mechanical pressure, membrane potential is integrated with signal transduction networks by affecting the conformation and clustering of proteins in the membrane 3,4 , as well as the transmembrane flux of key signaling ions 5,6 . Indeed, we show that important mechano-sensing pathways, YAP, Jnk and p38 7-121314 , are directly controlled by membrane potential. We further show that mechano-transduction via membrane potential plays a critical role in the homeostasis of epithelial tissues, setting tissue density by controlling proliferation and cell extrusion of cells. Moreover, a wave of depolarization triggered by mechanical stretch enhances the speed of wound healing. Mechano-transduction via membrane potential likely constitutes an ancient homeostatic mechanism in multi-cellular organisms, potentially serving as a steppingstone for the evolution of excitable tissues and neuronal mechano-sensing. The breakdown of membrane potential mediated homeostatic regulation may contribute to tumor growth.