Mechanochemical mechanism underlying intercellular Ca(2+) wave propagation and its crucial role in apoptotic cell extrusion.

Calcium (Ca(2+)) wave propagation plays a crucial role in intercellular communication. Elevation of cytosolic Ca(2+) (Ca(2+) transient) in a single cell is attributed to various Ca(2+) channels present in the plasma membrane and endoplasmic reticulum, whereas gap junctions contribute to propagation of Ca(2+) waves between cells. However, we found that Ca(2+) 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 Ca(2+) channels (MCCs) mediates the Ca(2+) wave propagation; an apoptotic cell shrinks accompanied by a Ca(2+) transient, followed by pulling the edges of neighboring cells, which opens MCCs in neighboring cells, resulting in Ca(2+) transients in these cells. Furthermore, Ca(2+) 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 Ca(2+) wave propagation and its significant role in ACE.