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DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport
Jeremiah Bernier-Latmani, … , Sanjiv A. Luther, Tatiana V. Petrova
Jeremiah Bernier-Latmani, … , Sanjiv A. Luther, Tatiana V. Petrova
Published December 1, 2015; First published November 3, 2015
Citation Information: J Clin Invest. 2015;125(12):4572-4586. https://doi.org/10.1172/JCI82045.
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Categories: Research Article Vascular biology

DLL4 promotes continuous adult intestinal lacteal regeneration and dietary fat transport

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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

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

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Figure 1

Unique organization of small intestinal stroma.

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Unique organization of small intestinal stroma.
Confocal microscope imag...
Confocal microscope images of adult mouse small intestinal villi after whole-mount immunostaining. (A) A dense blood capillary network (VEGFR2, green) lies in close proximity to intestinal epithelial cells (E-cadherin, red). (B) Adult lacteals (LYVE1, red) and villus blood vessels (PECAM1, green) in adult small intestine. (C) Pericytes (NG2, green, arrowheads) are closely associated with villus blood capillaries (VEGFR2, red). (D) αSMA (red) staining reveals a network of SMCs in the villi, located inside the blood capillary network (green). MM, muscularis mucosa; CM, circular muscle; LM, longitudinal muscle. (E) A subset of villus SMCs (αSMA, cyan) are in close proximity to lacteals (LYVE1, red). (F) Higher-magnification view of near lacteal villus SMCs (αSMA, cyan). (G) Terminal ends of villus SMCs (αSMA, red) interact with villus blood vessels (PECAM1, green). Nuclei are stained with DAPI (blue). Ep, epithelial cells. Scale bars: 50 μm, A–D; 20 μm, E; 10 μm, F; 5 μm, G.
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