Wound-induced Ca2+ wave propagates through a simple release and diffusion mechanism

Damage-associated molecular patterns (DAMPs) are critical mediators of information concerning tissue damage from damaged cells to neighboring healthy cells. ATP acts as an effective DAMP when released into extracellular space from damaged cells. Extracellular ATP receptors monitor tissue damage and activate a Ca2+ wave in the surrounding healthy cells. How the Ca2+ wave propagates through cells after a wound is unclear. Ca2+ wave activation can occur extracellularly via external receptors or intracellularly through GAP junctions. Three potential mechanisms to propagate the Ca2+ wave are source and sink, amplifying wave, and release and diffusion. Both source and sink and amplifying wave regulate ATP levels using hydrolysis or secretion, respectively, whereas release and diffusion relies on dilution. Here we systematically test these hypotheses using a microfluidics assay to mechanically wound an epithelial monolayer in combination with direct manipulation of ATP hydrolysis and release. We show that a release and diffusion model sufficiently explains Ca2+-wave propagation after an epithelial wound. A release and diffusion model combines the benefits of fast activation at short length scales with a self-limiting response to prevent unnecessary inflammatory responses harmful to the organism.