A progenitor cell population contributes to prenatal injury repair and neonatal antimicrobial defense in the small intestine

Summary The specialized types and functions of epithelial cells in the adult small intestine have been well elucidated, but remain poorly understood in the embryonic small intestine. Through integrating single-cell RNA sequencing with functional studies using mouse and organoid models, we identify small intestinal sentinel progenitor cells (SISPCs), marked by Lysozyme1 (Lyz1), in the embryonic and neonatal mouse small intestine. Distinct from Lyz1⁺ Paneth cells, SISPCs exhibit dynamic spatiotemporal patterning and stemness features during intestinal development. Notably, embryonic SISPCs display strong stemness potential in the proximal small intestine, whereas embryonic Lgr5⁺ cells exhibit greater stem potency in the distal region. In addition, SISPCs play a crucial role in the prenatal intestinal injury repair via the DUSP-p38 signaling axis and contribute to the neonatal antimicrobial defense. Our findings reveal SISPCs play a pivotal role in gut homeostasis and defense during development, and suggest them as potential therapeutic targets for developmental gut disorders.