Plenary Paper VASCULAR BIOLOGY Conditional ablation of LYVE-11 cells unveils defensive roles of lymphatic vessels in intestine and lymph nodes

Because of their unique structure and distribution, lymphatic vessels play specialized roles in 1-way drainage of interstitial fluid to the systemic circulation for tissue fluid homeostasis and 1-way transfer of immune cells from peripheral tissue to draining lymph nodes for immune cell trafficking. Moreover, they are critical in 1-way transport of absorbed dietary fats and drugs as lacteals in the intestinal villi and provide a route for tumor dissemination in the periphery of solid tumors. Indeed, lymphatic vessels appear to have highly versatile structures and functions that intimately interact with their surrounding tissues, especially blood vessels in each organ. Like blood vessels, the structure and function of lymphatic vessels in each organ could be organotypic. However, to date, an organotypic role of lymphatic vessels in the maintenance of tissue homeostasis is only beginning to be understood. Identification in recent decades of several key regulators and markers specific to lymphatic endothelial cells has accelerated findings about lymphatic vessel genesis, detailed structure, additional roles, and interactions with other cells and tissues. For example, lymphatic vessels are formed from the cardinal vein via a transdifferentiation process under Prox1 activity at least in mammals during embryonic development. Lymphatic endothelial cells in the initial lymphatic vessels have discontinuous buttonlike junctions that allow entry of fluid and certain immune cells into the vessel lumen through flaplike openings that form the primary lymphatic valves. Lymphatic endothelial cells in the collecting lymphatic vessels have continuous zipperlike interendothelial junctions, periendothelial smooth muscle cell layers, and valves for propelling unidirectional lymph flow without leakage. Furthermore, lymphatic vessels reciprocally play a dual role in inducing and resolving inflammation. Lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) is one of the most specific and widely used lymphatic endothelial cell markers. It is first expressed in a few transdifferentiating endothelial cells from venous endothelial cells to lymphatic endothelial cells, which line the anterior cardinal vein of mice at embryonic days 9.0 to 9.5, and is currently considered the first indicator of lymphatic endothelial competence. In adults, LYVE-1 expression in larger collecting lymphatic vessels decreases but remains high in small lymphatic capillaries at each organ. Constitutive and conditional lineage ablation in vivo allows investigation of cell function in the context of the whole organism. The system involving the inducible diphtheria toxin receptor (iDTR), part of the heparin-binding epidermal growth factor–like growth factor, has been introduced as a useful method for conditional lineage ablation. Murine cells, unlike primate cells, are insensitive to diphtheria toxin (DT) because of its low affinity for rodent heparinbinding epidermal growth factor–like growth factor. Cell surface expression of DTR allows receptor-mediated endocytosis of DT, which induces rapid apoptosis of the target cell. Once introduced into a cell, even a single DT fragment is sufficient to kill the cell, making the DTR system very sensitive and specific. Taking advantage