Organ injury accelerates stem cell differentiation by modulating a fate-transducing lateral inhibition circuit.

Injured epithelial organs must rapidly replace damaged cells to restore barrier integrity and physiological function. In response, injury-born stem cell progeny differentiate faster compared to healthy-born counterparts, yet the mechanisms that pace differentiation are unclear. Using the adult Drosophila intestine, we find that injury speeds cell differentiation by altering the lateral inhibition circuit that transduces a fate-determining Notch signal. During healthy intestinal turnover, a balanced ratio of terminal (Notch-active) and stem (Notch-inactive) fates arises through canonical lateral inhibition feedback, in which mutual Notch-Delta signaling between two stem cell daughters evolves to activate Notch and extinguish Delta in exactly one cell. When we damage intestines by feeding flies toxin, mutual signaling persists, but a cytokine relay from damaged cells to differentiating daughters prevents the Notch co-repressor Groucho from extinguishing Delta. Despite Delta persistence, injured organs preserve the Notch-inactive stem cell pool; thus, fate balance does not hinge on an intact circuit. Mathematical modeling predicts that increased Delta prompts faster Notch signaling; indeed, in vivo live imaging reveals that the real-time speed of Notch signal transduction doubles in injured guts. These results show that in tissue homeostasis, lateral inhibition feedback between stem cell daughters throttles the speed of Notch-mediated fate determination by constraining Delta. Tissue-level damage signals relax this constraint to accelerate cell differentiation for expedited organ repair.