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Cell. 2019 Nov 14;179(5):1144-1159.e15. doi: 10.1016/j.cell.2019.10.015. Epub 2019 Nov 7.

Long-Term Culture Captures Injury-Repair Cycles of Colonic Stem Cells.

Author information

1
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
2
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
3
Boehringer Ingelheim Pharmaceuticals, Immunology and Respiratory Disease Research, Ridgefield, CT 06877, USA.
4
Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
5
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA. Electronic address: stappenb@wustl.edu.

Abstract

The colonic epithelium can undergo multiple rounds of damage and repair, often in response to excessive inflammation. The responsive stem cell that mediates this process is unclear, in part because of a lack of in vitro models that recapitulate key epithelial changes that occur in vivo during damage and repair. Here, we identify a Hopx+ colitis-associated regenerative stem cell (CARSC) population that functionally contributes to mucosal repair in mouse models of colitis. Hopx+ CARSCs, enriched for fetal-like markers, transiently arose from hypertrophic crypts known to facilitate regeneration. Importantly, we established a long-term, self-organizing two-dimensional (2D) epithelial monolayer system to model the regenerative properties and responses of Hopx+ CARSCs. This system can reenact the "homeostasis-injury-regeneration" cycles of epithelial alterations that occur in vivo. Using this system, we found that hypoxia and endoplasmic reticulum stress, insults commonly present in inflammatory bowel diseases, mediated the cyclic switch of cellular status in this process.

KEYWORDS:

HopX; Lgr5; Transwell; air-liquid interface; colitis; colon; hypoxia; intestine; stem cell; unfolded protein response

PMID:
31708126
DOI:
10.1016/j.cell.2019.10.015
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