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Our data suggest well-characterized drugs (already approved for human use) might be exploited to control adult stem cell-driven pattern formation during the regeneration of complex structures. Using this chemical genetics approach, we demonstrate that membrane voltage controls head-versus-tail identity during planarian regeneration. H +,K +-ATPase-independent manipulation of membrane potential with ivermectin confirms that depolarization drives head formation, even at posterior-facing wounds. Utilizing the highly specific inhibitor, SCH-28080, our data reveal that H +,K +-ATPase-mediated membrane depolarization is essential for anterior gene expression and brain induction. Here, we develop a pharmacological method to target ion transporters, uncovering a role for membrane voltage as a key regulator of anterior polarity in regenerating planaria. Exploiting endogenous ion transport for regenerative therapies will require direct regulation of membrane voltage. Biophysical signaling is required for both embryonic polarity and regenerative outgrowth.

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