DLL4 promotes continuous lacteal regeneration in the adult small intestine.
(A) During normal homeostasis the intestinal villi are subject to many stressors, including dietary fat, the gut microbiota, and villus movements, which lacteals encounter as chylomicrons, TLR ligands, and mechanical stress, respectively. In normal mice, VEGFC/D signaling, through VEGFR2 and VEGFR3, promotes lacteal DLL4 expression and Notch signaling, thus maintaining LEC survival, sprouting, and migration to replace damaged cells. Furthermore, LECs in lacteals have both continuous and discontinuous adherens junctions, balancing the need for continuous regeneration with the need for efficient chylomicron uptake. (B) In the absence of DLL4, lacteals are unable to undergo remodeling and have impaired survival and migration and thus are not able to maintain the normal length in villi. Lymphatic Dll4 deletion also promotes a shift from mixed adherens junctions to mostly continuous junctions, contributing to inefficient chylomicron uptake and transport. MLN, mesenteric lymph node.
Bernier-Latmani J., JCI, 2015