Inflammatory memory primes the intestine for enhanced regenerative potential

How do inflammation and activation of the regenerative genetic program affect intestinal epithelial cell behavior and shape responses to future injuries? Following injury, which typically induces intestinal stem cell (ISC) death, regeneration occurs via the proliferation of surviving ISCs and via cellular plasticity through dedifferentiation of progenitors and committed cells. While inflammation and cellular plasticity are hallmarks of regeneration, its long-term effects on epithelial cell behavior are not well understood. Using single cell multiomics, we demonstrate that inflammatory exposure and cellular plasticity imprint a lasting transcriptional and epigenetic memory on ISCs and their progeny, priming them for enhanced repair after subsequent injuries. Mechanistically, we identify IFN-γ as a critical driver of this primed regenerative state. These findings uncover how prior inflammation reprograms regenerative capacity, with implications for tissue resilience and disease susceptibility. The intestine remembers past injury. Arozamena and colleagues reveal that transcriptional and epigenetic memory accelerates future repair, with IFN-gamma encoding inflammatory memory and dedifferentiation leaving a distinct regenerative imprint.