Lgr5+ Gastric Stem Cells Divide Symmetrically to Effect Epithelial Homeostasis in the Pylorus

• Multiple Lgr5+ stem cells per gastric unit contribute to pyloric epithelial homeostasis
• The majority of Lgr5+ pyloric stem cells typically divide symmetrically
• Neutral drift occurs within the Lgr5+ stem cell compartment of individual glands
• Dominant stem cells expand laterally via gland fission over time

SummaryThe pyloric epithelium continuously self-renews throughout life, driven by limited reservoirs of resident Lgr5+ adult stem cells. Here, we characterize the population dynamics of these stem cells during epithelial homeostasis. Using a clonal fate-mapping strategy, we demonstrate that multiple Lgr5+ cells routinely contribute to epithelial renewal in the pyloric gland and, similar to what was previously observed in the intestine, a balanced homeostasis of the glandular epithelium and stem cell pools is predominantly achieved via neutral competition between symmetrically dividing Lgr5+ stem cells. Additionally, we document a lateral expansion of stem cell clones via gland fission under nondamage conditions. These findings represent a major advance in our basic understanding of tissue homeostasis in the stomach and form the foundation for identifying altered stem cell behavior during gastric disease.

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