Abstract
SummaryThe 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.
Highlights
The intestinal epithelium is the physical barrier separating luminal contents from the underlying stroma
We present the identification of a colitis-associated regenerative stem cell (CARSC) population marked by Hopx expression in mouse models of colitis
We demonstrate that Hopx+ CARSCs arise during the reparative stage of colitis, preceded by an injury phase when Lgr5/Hopx double negative atrophic crypts are prevalent near areas of ulcerations
Summary
The intestinal epithelium is the physical barrier separating luminal contents from the underlying stroma Disruptions of this barrier, whether caused by infection, excessive dysregulated inflammation, vascular insults, or iatrogenic causes must be swiftly repaired to minimize the exposure of the host to insults arising from otherwise contained luminal contents. Insults that superficially damage the mucosa and focally remove differentiated epithelial cells are quickly repaired by the migration of adjacent epithelial cells (Feil et al, 1989; Lacy, 1988). This restitution normally occurs within minutes to hours (Feil et al, 1989; Lacy, 1987). In scenarios where more severe lesions occur that include crypt loss, stem cells in the crypts positioned adjacent to the area of injury are mobilized to repair the damage by forming wound channels (Miyoshi et al, 2012; Seno et al, 2009)
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