UCSF

Damage to mammalian organs elicits an inflammatory response and is repaired by tissue remodeling and cell proliferation. Healing therefore requires a complex interplay between immune cells and tissue resident progenitor cells. In the intestine, the epithelial surface must be repaired after breaches to the barrier caused by injury or infection. However, how intestinal stem and progenitor cells sense and respond to damage is relatively unknown. Here, we examined how epithelial crypt progenitors respond to damage driven by the natural parasite, Heligmosomoides polygyrus (Hp). Damage to the epithelial barrier by Hp larvae induced an inflammatory granulomatous reaction and a local regenerative response in epithelial crypt progenitors. Paradoxically, markers of homeostatic intestinal stem cells, including Lgr5, were absent in granuloma-associated crypts. Concurrently, immune cells responding to Hp infection drove the expression of Sca-1 on regenerative epithelium through IFNγ cytokines. Several other non-infectious models of intestinal damage induced similar responses in the crypt, suggesting that Hp elicited a conserved response to injury. In Hp infections, regenerative Sca-1+ cells formed undifferentiated fetal-like spheroids in in vitro culture, which were distinct from adult organoids stemming from unaffected crypts from the same mice. Furthermore, regenerative crypts adapted a transcriptional signature resembling the developing fetal intestine, and a subset of Sca-1+ cells were undifferentiated and enriched for fetal markers. Together, our functional and transcriptional analysis suggested that regenerative Sca-1+ crypt cells were developmentally reprogrammed to a fetal-like state. We speculate that fetal reprogramming is a critical mechanism for maintaining intestinal integrity after injury. By recapitulating aspects of fetal development, the intestinal epithelium may unlock proliferative capacity silenced during homeostasis.