Bioenergetic Coupling to Transcriptional States Shapes Cooperative Regeneration

Supporting the viability of neighboring cells is a fundamental component of cooperative regeneration. How do individual cells acquire such cooperative bias? Recent models of cell memory propose that bioenergetic coupling allows cells to link extracellular signals, such as calcium waves, with ATP gain, thereby increasing fitness when surrounding tissue prospers. However, tissues often exhibit generalized cooperative responses independent of any particular molecular cue. We hypothesized that metabolic conditioning enables cells to associate bioenergetic surplus directly with abstract transcriptional states of neighbors, learning that a pro-regenerative program forecasts their own energetic benefit. In four organoid-based assays using 1,500 clonally labeled epithelial clusters, intracellular ATP levels were made to be congruently or incongruently predicted by adjacent clusters’ transcriptional signatures. Clusters experiencing congruent conditioning subsequently exhibited heightened expression of cooperative morphogen genes when challenged with novel wounds. The energetic weights assigned to transcriptional states further biased collective migration and gap-junction-mediated resource sharing. These findings show that associative metabolic conditioning of abstract gene-expression states can engender generalizable cooperative morphogenesis and modulate tissue-level repair strategies.