Patterned morphogenesis of epithelial wound detection and healing

When a sheet of epithelial cells is wounded, cells around the wound are recruited from a near quiescent state to reactivate motility and proliferation behaviors similar to early development. Importantly, the epithelium around the wound must be appropriately patterned to drive different cell behaviors in proximal and distal regions. As the first stage of this patterning, surrounding epithelial cells undergo a dramatic increase in cytosolic calcium. This increase occurs quickly: calcium floods into damaged cells within 0.1 s, moves into adjacent cells over ~20 s, and appears in a much larger set of surrounding cells via a delayed second expansion over 40-300 s. Nonetheless, increased calcium is a reporter; cells must detect wounds even earlier. Using the calcium response as a proxy for wound detection, we identify an upstream G-protein-coupled-receptor (GPCR) signaling pathway, including the receptor and its protease-activated chemokine ligand. We present experimental and computational evidence delineating the mechanisms by which the calcium signaling patterns are established and through which cells interpret the calcium signals to drive wound repair behaviors.