Persistent Fibrosis Linked to Bioelectric Overactivity in the Blastema Organizer

Excessive scarring is associated with heightened bioelectric activity of epithelial and mesenchymal cells along the wound–regeneration axis. We show that at the peak of acute wound closure, superficial blastema organizer fibroblasts (BOFs) that transmit patterning cues to the contralateral epithelium transiently reduce their intrinsic depolarization and, consequently, calcium spike frequency. When epithelial integrity is restored, the membrane potential of these cells returns to baseline. Using voltage-sensitive dyes, patch-clamp recordings and biophysical modeling, we found that an up-regulation of a transient outward K+ conductance (IA) underlies the hyperpolarization of BOFs in acute regenerative conditions. In chronic fibrotic states, no modulation of IA was observed, and BOFs exhibit sustained depolarization and elevated spiking. Our results reveal a differential bioelectric tuning of organizer fibroblasts in acute and chronic repair, suggesting a regulatory mechanism that, in the acute setting, tempers blastemal output and, if absent, may facilitate fibrotic chronification.