Epithelial surfaces form critical barriers to the outside world and are continuously renewed by adult stem cells1. Whereas dynamics of epithelial stem cells 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, a co-evolved pathosymbiont of mice, to assess the epithelial response to disruption of the mucosal barrier. H. polygyrus disrupts tissue integrity by penetrating the duodenal mucosa, where it develops while surrounded by a multicellular granulomatous infiltrate2. Crypts overlying larvae-associated granulomas did not express intestinal stem cell markers, including Lgr53, in spite of continued epithelial proliferation. Granuloma-associated Lgr5− crypt epithelium activated an interferon-gamma (IFN-γ)-dependent transcriptional program, highlighted by Sca-1 expression, and IFN-γ-producing immune cells were found in granulomas. A similar epithelial response accompanied systemic activation of immune cells, intestinal irradiation, or ablation of Lgr5+ intestinal stem cells. When cultured in vitro, granuloma-associated crypt cells formed spheroids similar to those formed by fetal epithelium, and a sub-population of H. polygyrus-induced cells activated a fetal-like transcriptional program, demonstrating that adult intestinal tissues can repurpose aspects of fetal development. Therefore, re-initiation of the developmental program represents a fundamental mechanism by which the intestinal crypt can remodel itself to sustain function after injury.
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We thank M. Consengco, R. D’Urso, J. Ming, A. Rathnayake, N. Wang and Z. Wang for technical expertise, the UCSF Institute of Human Genetics Core and Functional Genomics Core for performing the RNA-seq experiments, members of the Klein and Locksley labs for discussions, and K. Lindquist for advice on GSEA analysis. This work was supported by the National Institutes of Health (AI026918, AI030663 and U01DK103147 from the Intestinal Stem Cell Consortium—a collaborative research project funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases), the Howard Hughes Medical Institute (HHMI), the California Institute for Regenerative Medicine (RN3-06525) and the Sandler Asthma Basic Research Center at the University of California, San Francisco. A.K.S. is an HHMI Fellow. Y.M.N. was awarded a Genentech Graduate Fellowship in 2014.
Nature thanks A. Hanash, T. Sato, S. Takashima and the other anonymous reviewer(s) for their contribution to the peer review of this work.