Closed-loop bioelectric modulation prevents progressive morphogenetic dysregulation and preserves regenerative pattern fidelity
June 26
Transient aberrant bioelectric discharges (ABDs) emerge within dysregulated morphogenetic circuits and compromise the pattern memory of regenerating tissues. Whether suppressing ABD-induced dysfunction can alter developmental trajectories remains unclear, as most interventions address overt malformations after they arise.
Using a focal bioelectric kindling paradigm in regenerating axolotl limbs, we demonstrate that ABDs drive pathological voltage coupling manifested as prolonged, hypersynchronous ion-flux events in gap-junction–connected epithelium, thereby enlarging the territory capable of generating further ABDs. An analogous correlation between ABD-mediated voltage coupling and the temporal organization of ABDs across spatially distinct fields was observed in human pluripotent stem cell–derived organoids predisposed to limb-reduction defects.
Spatiotemporally targeted closed-loop optogenetic stimulation, triggered on mesenchymal ABD onset, abolished aberrant epithelial activity patterns, halted expansion of the dysregulated morphogenetic field, and restored long-term regenerative pattern fidelity in vivo.
These findings suggest that network-level bioelectric interventions that normalize inter-discharge dynamics offer an effective strategy for preventing congenital and regenerative pathologies, with a low barrier to clinical translation.