Bernier-Latmani Jeremiah, Cisarovsky Christophe, Demir Cansaran Saygili, Bruand Marine, Jaquet Muriel, Davanture Suzel, Ragusa Simone, Siegert Stefanie, Dormond Olivier, Benedito Rui, Radtke Freddy, Luther Sanjiv A, Petrova Tatiana V
J Clin Invest. 2015 Nov 3;125(12):4572-86. doi: 10.1172/JCI82045.
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.
小肠是一个动态且复杂的器官，其特征在于上皮细胞持续更新以及各种细胞类型与微生物群之间的相互作用。小肠的淋巴管，即乳糜管，在膳食脂肪吸收和肠道免疫反应中发挥关键作用；然而，关于乳糜管功能的分子调控却知之甚少。在此，我们对小肠基质进行了高分辨率分析，并确定乳糜管处于一种永久再生、增殖的状态，这与胚胎期淋巴管生成或在其他组织中观察到的静止淋巴管不同。我们进一步证明，这种持续的再生过程由Notch信号介导，并且乳糜管中Notch配体Delta样蛋白4（DLL4）的表达需要VEGFR3和VEGFR2的激活。此外，淋巴管内皮细胞中Dll4的基因失活导致乳糜管退化和膳食脂肪摄取受损。我们提出，这种缓慢的淋巴管再生模式对于满足肠道淋巴管因持续暴露于膳食脂肪和机械应变而对持续维持的独特需求以及有效摄取脂肪和免疫细胞是必要的。我们的研究揭示了组织特化如何塑造淋巴管反应，并揭示了持续的DLL4信号在成人淋巴管功能中的作用。
