Mechanochemical mechanism underlying intercellular Ca2+ wave propagation and its crucial role in apoptotic cell extrusion

Abstract

Calcium (Ca2+) wave propagation plays a crucial role in intercellular communication. Elevation of cytosolic Ca2+ (Ca2+ transient) in a single cell is attributed to various Ca2+ channels present in the plasma membrane and endoplasmic reticulum, whereas gap junctions contribute to propagation of Ca2+ waves between cells. However, we found that Ca2+ waves propagate without gap junctions during apoptotic cell extrusion (ACE). Mechanistically, we identified that a chain reaction of mechano-signal transduction from proximal to distal cells through the mechanosensitive Ca2+ channels (MCCs) mediates the Ca2+ wave propagation; an apoptotic cell shrinks accompanied by a Ca2+ transient, followed by pulling the edges of neighboring cells, which opens MCCs in neighboring cells, resulting in Ca2+ transients in these cells. Furthermore, Ca2+ wave propagation promotes Rac-Arp2/3 pathway-mediated polarized collective migration, generating approximately 1 kPa of force toward extruding cells. Our results uncovered a mechanochemical mechanism of Ca2+ wave propagation and its significant role in ACE.