Lgr5⁺ cells regulate small intestinal morphogenesis before villification.

Lgr5 marks both adult intestinal stem cells and embryonic intestinal stem/progenitor cells. However, the stemness properties and physiological roles of embryonic intestinal Lgr5⁺ cells prior to villification (PVLCs) remain largely unknown. In this study, we show that PVLCs in the embryonic small intestine exhibit region-specific stemness, with progressively enhanced stemness potential from the proximal to distal region. Through inducible cell ablation and gene knockout experiments, we demonstrate that PVLCs regulate small intestinal morphogenesis via Hedgehog signaling in a region-dependent manner, with distal morphogenesis being more dependent on this mechanism. This study reveals the stemness and functional roles of PVLCs in the embryonic small intestine prior to villification, highlighting regionalized cellular heterogeneity as a critical determinant of intestinal morphogenesis.