The small intestine is a dynamic and complex organ that is characterized by constant epithelium turnover and crosstalk among various cell types and the microbiota. Lymphatic capillaries of the small intestine, called lacteals, play key roles in dietary fat absorption and the gut immune response; however, little is known about the molecular regulation of lacteal function. Here, we performed a high-resolution analysis of the small intestinal stroma and determined that lacteals reside in a permanent regenerative, proliferative state that is distinct from embryonic lymphangiogenesis or quiescent lymphatic vessels observed in other tissues. We further demonstrated that this continuous regeneration process is mediated by Notch signaling and that the expression of the Notch ligand delta-like 4 (DLL4) in lacteals requires activation of VEGFR3 and VEGFR2. Moreover, genetic inactivation of
Jeremiah Bernier-Latmani, Christophe Cisarovsky, Cansaran Saygili Demir, Marine Bruand, Muriel Jaquet, Suzel Davanture, Simone Ragusa, Stefanie Siegert, Olivier Dormond, Rui Benedito, Freddy Radtke, Sanjiv A. Luther, Tatiana V. Petrova
DLL4 is required for lacteal length maintenance.