Dataset Information

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.

SUBMITTER: Bernier-Latmani J

PROVIDER: S-EPMC4665794 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport.

Bernier-Latmani Jeremiah J Cisarovsky Christophe C Demir Cansaran Saygili CS Bruand Marine M Jaquet Muriel M Davanture Suzel S Ragusa Simone S Siegert Stefanie S Dormond Olivier O Benedito Rui R Radtke Freddy F Luther Sanjiv A SA Petrova Tatiana V TV

The Journal of clinical investigation 20151103 12

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 permanen ...[more]

PMID: 26529256

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Project description:The effects of excessive dietary iron intake on the body have been an important topic. The purpose of this study was to investigate the effects of high-dose iron on intestinal damage and regeneration in dextran sodium sulfate (DSS)-induced colitis model mice. A total of 72 8-week-old adult C57BL/6 mice were randomly divided into two dietary treatment groups: the basal diet supplemented with 45 (control) and 450 mg/kg iron (high-iron) from ferrous sulfate. The mice were fed different diets for 2 weeks, and then 2.5% DSS was orally administered to all mice for 7 days. Samples of different tissues were collected on days 0, 3, and 7 post administration (DPA). High-iron treatment significantly decreased the relative weight of the large intestine at 7 DPA but not at 0 DPA or 3 DPA. High dietary iron increased the jejunal villus width at 0 DPA, decreased the villus width and the crypt depth of the jejunum at 3 DPA, and decreased the number of colonic crypts at 7 DPA. Meanwhile, high dietary iron decreased the number of goblet cells in the jejunal villi and the Paneth cells in the jejunal crypts at 0 DPA, increased the number of goblet cells per crypt of the colon at 3 DPA, and the number of Paneth cells in the jejunal crypts, the goblet cells in the colon, the Ki67-positive proliferating cells in the colon, and the Sex-determining region Y-box transcription factor 9+ (SOX9) cells in the jejunum crypts and colon at 7 DPA. The organoid formation rate was increased by high-iron treatments at 3 DPA and 7 DPA. High dietary iron treatment decreased the mRNA level of jejunal jagged canonical Notch ligand 2 (Jag-2) at 0 DPA and bone morphogenetic protein 4 (Bmp4) and neural precursor cell-expressed developmentally downregulated 8 (Nedd8) in the jejunum and colon at 7 DPA, whereas it increased the mRNA expression of the serum/glucocorticoid-regulated kinase 1 (Sgk1) in the colon at 3 DPA. The results suggested that a high dose of iron aggravated intestinal injury but promoted intestinal repair by regulating intestinal epithelial cell renewal and intestinal stem cell activity in adult mice with colitis.

Project description:The Na(+)-dependent glucose transporter SGLT1 and the facilitated fructose transporter GLUT5 absorb sugars from the intestinal lumen across the brush-border membrane into the cells. The activity of these transport systems is known to be regulated primarily by diet and development. The cloning of these transporters has led to a surge of studies on cellular mechanisms regulating intestinal sugar transport. However, the small intestine can be a difficult organ to study, because its cells are continuously differentiating along the villus, and because the function of absorptive cells depends on both their state of maturity and their location along the villus axis. In this review, I describe the typical patterns of regulation of transport activity by dietary carbohydrate, Na(+) and fibre, how these patterns are influenced by circadian rhythms, and how they vary in different species and during development. I then describe the molecular mechanisms underlying these regulatory patterns. The expression of these transporters is tightly linked to the villus architecture; hence, I also review the regulatory processes occurring along the crypt-villus axis. Regulation of glucose transport by diet may involve increased transcription of SGLT1 mainly in crypt cells. As cells migrate to the villus, the mRNA is degraded, and transporter proteins are then inserted into the membrane, leading to increases in glucose transport about a day after an increase in carbohydrate levels. In the SGLT1 model, transport activity in villus cells cannot be modulated by diet. In contrast, GLUT5 regulation by the diet seems to involve de novo synthesis of GLUT5 mRNA synthesis and protein in cells lining the villus, leading to increases in fructose transport a few hours after consumption of diets containing fructose. In the GLUT5 model, transport activity can be reprogrammed in mature enterocytes lining the villus column. Innovative experimental approaches are needed to increase our understanding of sugar transport regulation in the small intestine. I close by suggesting specific areas of research that may yield important information about this interesting, but difficult, topic.

Dataset Information

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport.

Publications

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport.

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