Lgr5-Expressing Chief Cells Drive Epithelial Regeneration and Cancer in the Oxyntic Stomach

Adult stem cells residing within tubular glands of the corpus epithelium are believed to fuel daily tissue renewal, but their identity remains controversial. Lgr5, marks both homeostatic stem cells and reserve stem cells in multiple tissues. Here, we report Lgr5 expression in a subpopulation of chief cells in mouse and human corpus glands. Using a new, non-variegated Lgr5-2A-CreERT2 mouse model, we show by cell fate mapping that Lgr5-expressing chief cells do not behave as corpus stem cells under homeostatic conditions, but are recruited to function as stem cells to effect epithelial renewal following injury. In vivo ablation of the Lgr5+ cells severely impairs epithelial homeostasis in the corpus, indicating an essential role in maintaining the resident stem cell pool. We additionally define the Lgr5+ chief cells as a major cell of origin of gastric metaplasia. These findings reveal clinically relevant insights into tissue homeostasis, repair and cancer in the corpus.

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