Epithelial surfaces form critical barriers to the outside world and are continuously renewed by adult stem cells. Whereas epithelial stem cell dynamics during homeostasis are increasingly well understood, how stem cells are redirected from a tissue-maintenance program to initiate repair after injury remains unclear. Here, we examined infection by Heligmosomoides polygyrus (Hp), a co-evolved pathosymbiont of mice, to assess the epithelial response to disruption of the mucosal barrier. Hp disrupts tissue integrity by penetrating the duodenal mucosa, where it develops while surrounded by a multicellular granulomatous infiltrate. Unexpectedly, intestinal stem cell (ISC) markers, including Lgr5, were lost in crypts overlying larvae-associated granulomas, despite continued epithelial proliferation. Granuloma-associated Lgr5− crypt epithelia activated an interferon-gamma (IFNγ)-dependent transcriptional program, highlighted by Sca-1 expression, and IFNγ-producing immune cells were found in granulomas. A similar epithelial response accompanied systemic activation of immune cells, intestinal irradiation, or ablation of Lgr5+ ISCs. Granuloma-associated crypt cells generated fetal-like spheroids in culture, and a sub-population of Hp-induced cells activated a fetal-like transcriptional program, demonstrating that adult intestinal tissues can repurpose aspects of fetal development. Thus, re-initiation of the developmental program represents a fundamental mechanism by which the intestinal crypt can remodel to sustain function after injury.
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