title: DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport.
abstract: 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 Dll4 in lymphatic endothelial cells led to lacteal regression and impaired dietary fat uptake. We propose that such a slow lymphatic regeneration mode is necessary to match a unique need of intestinal lymphatic vessels for both continuous maintenance, due to the constant exposure to dietary fat and mechanical strain, and efficient uptake of fat and immune cells. Our work reveals how lymphatic vessel responses are shaped by tissue specialization and uncover a role for continuous DLL4 signaling in the function of adult lymphatic vasculature.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Bernier-Latmani
authors.forename: Christophe
authors.initials: C
authors.lastname: Cisarovsky
authors.forename: Cansaran Saygili
authors.initials: CS
authors.lastname: Demir
authors.forename: Marine
authors.initials: M
authors.lastname: Bruand
authors.forename: Muriel
authors.initials: M
authors.lastname: Jaquet
authors.forename: Suzel
authors.initials: S
authors.lastname: Davanture
authors.forename: Simone
authors.initials: S
authors.lastname: Ragusa
authors.forename: Stefanie
authors.initials: S
authors.lastname: Siegert
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
authors.forename: Rui
authors.initials: R
authors.lastname: Benedito
authors.forename: Freddy
authors.initials: F
authors.lastname: Radtke
authors.forename: Sanjiv A
authors.initials: SA
authors.lastname: Luther
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Petrova
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D004041:Dietary Fats / Q000378:metabolism* / Q000494:pharmacology; D007421:Intestine, Small / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D004041:Dietary Fats; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2