Opposite regulation of epithelial relay cell excitability during acute regenerative response versus chronic non-healing injury
June 23
Heightened tissue sensitivity after injury is frequently linked to elevated activity of peripheral and central cell networks along the wound axis. Here we show that, at the peak of an acute regenerative episode, superficial dermal epithelial relay cells that transmit injury-derived information to the subepithelial mesenchyme down-regulate their intrinsic excitability and, consequently, spike output. When regeneration completes, the excitability of these cells returns to baseline. Combining patch-clamp recordings with biophysically constrained simulations, we found that an up-regulation of the transient outward potassium A-current (IA) underlies the decreased excitability of dermal relay cells in the acute phase. In a chronic, non-healing context, IA does not change, and dermal relay cells instead display increased intrinsic excitability and firing. Our findings reveal a phase-specific modulation of epithelial relay cell excitability in acute versus chronic injury settings, suggesting a regulatory mechanism that, during successful regeneration, tempers signal output from the wound edge and, when absent, may facilitate transition to persistent, maladaptive wound states.