Tissue-level mechanisms underlying the inhibitory control of pattern memory during regeneration

Regenerative growth and architectural fidelity both depend on the capacity of a tissue to arrest morphogenetic programs when appropriate. Over the past two decades, convergent evidence has indicated that a domain-general inhibitory circuit located in the anterior-lateral wound epidermis fulfils this role. Current models of morphogenetic inhibition, however, are derived largely from studies of proliferation arrest—an experimentally convenient paradigm that does not engage suppression of pattern memory and therefore cannot reveal the unique mechanisms required for that process. Here, we synthesise recent work that interrogates how organisms terminate a key driver of regeneration: the reactivation of latent pattern templates. This research demonstrates that pattern-memory arrest recruits the same anterior-lateral epidermal bioelectric machinery used for proliferation arrest, supporting the idea of a shared, domain-general inhibitory system. Critically, successful control also depends on a distinct epidermal–mesenchymal signalling axis that determines the efficacy of inhibition. Within this axis, chloride-mediated hyperpolarisation of mesenchymal progenitors modulates the impact of epidermal commands on pattern-memory circuitry. Disruption of this bioelectric shunting in the mesenchyme leads to failure of inhibition and results in uncontrolled, ectopic outgrowths. These findings position mesenchymal disinhibition as a trans-contextual driver of aberrant regeneration, linking the epidermal–mesenchymal control pathway to experimental models of congenital malformation and fibrotic scarring. We propose that deficits in pattern-memory arrest represent a unifying mechanism underlying diverse developmental pathologies characterised by excessive or misplaced tissue growth. Targeting the epidermal–mesenchymal inhibitory circuit, and in particular the bioelectric state of progenitor fields, offers a promising frontier for therapeutic modulation of regenerative outcomes.