Mechanical Stretch Triggers Rapid Epithelial Cell Division Through the Stretch-Activated Channel Piezo1

Abstract

Despite acting as a barrier for the organs they encase, epithelial cells turnover at some of the fastest rates in the body. In order to maintain barrier function, cell division must be linked to cell death. How do the number of dying cells match those dividing to maintain constant numbers? We previously found that when epithelial cells become too crowded, they activate the stretch-activated channel Piezo1 to trigger extrusion of cells that later die. Conversely, what controls epithelial cell division to balance cell death at steady state? Here, we find that cell division occurs in regions of low cell density, where epithelial cells are stretched. Stretching epithelia either mechanically or by wounding causes cells to rapidly enter mitosis and this response also requires Piezo1. Stretch-activation of Piezo1 triggers a population of epithelial cells in early G2 that are poised for repair to produce cyclin B and enter mitosis following stretch. We find that Piezo1 localization varies depending upon epithelial cell density. In sparse regions, Piezo1 localizes to the plasma membrane, where it can mechanically sense stretch tensions to activate calcium currents. In cell dense regions, Piezo1 localizes to large cytoplasmic aggregates where it may better sense crowding to induce extrusion. Because Piezo1 senses both mechanical crowding and stretch, it may act as a homeostatic sensor to control epithelial cell numbers by driving extrusion and apoptosis when cells are too crowded and cell division when they are too sparse.