Rich lymphatic vessel (LV) networks supply the skin dermis and mucosal membranes covering major organs, including the respiratory tract, nasopharyngeal cavity, intestine, mesentery, diaphragm, heart, and lung. LVs are lacking or very sparse in bone, bone marrow, adipose tissue, heart myocardium and skeletal muscles, and parenchymal tissues of brain, liver, kidney, and endocrine organs, such as the adrenal or thyroid gland. Presumably, these organs are devoid of LVs because of scarce interstitial fluid or the presence of an alternative drainage system, such as fenestrated blood vessels (BVs). Interstitial fluid is drained into specialized blind-ended lymphatic capillaries, which connect and converge into gradually larger collecting LVs and lymphatic ducts that empty into the subclavian vein. Lymphatic endothelial cells (LECs) of lymphatic capillaries are surrounded by a thin, discontinuous basement membrane, lack perivascular cells, and have discontinuous “button-like” cell junctions (Baluk et al., 2007). They readily sense changes in interstitial pressure via specialized anchoring filaments, which can modulate the opening of “flap valves” in-between the button junctions to allow fluid entry. It is also through these flap valves that immune cells enter lymphatic capillaries. Unidirectional lymph flow in collecting vessels is promoted by numerous intraluminal valves and coordinated contraction of LV smooth muscle cells (SMCs; Schulte-Merker et al., 2011; Sabine et al., 2016). LECs represent a distinct endothelial cell (EC) lineage, and

LVs are frequently distinguished from BVs based on their expression of the transcription factor prospero homeobox-1 (Prox1), transmembrane O-glycoprotein podoplanin (also known as gp38), vascular endothelial growth factor receptor 3 (VEG FR3; also known as Flt4), neuropilin-2, and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE1; Tammel a and Alitalo, 2010; Alitalo, 2011; Aspelund et al., 2016). LVs have traditionally been regarded as passive conduits for fluid and some immune cells, but this perspective has been enormously updated with the discovery of novel structures, origins, and functions of LVs in several organs. Organ-specific lymphatic capillary LECs display remarkable heterogeneity and plasticity, and acquire specialized functional properties adapted to the local microenvironment. Understanding organotypic LEC differentiation and function can help in designing more effective therapeutic and regenerative strategies to cure a wider spectrum of common human diseases in which LVs have been shown to play major roles (Tammela and Alitalo, 2010; Alitalo, 2011; Aspelund et al., 2016). Advances in general physiology and pathology, development, lymphedema, and tumor lymphangiogenesis are already covered by excellent recent reviews (Tammela and Alitalo, 2010; Alitalo, 2011; Mortimer and Rockson, 2014; Aspelund et al., 2016; Dieterich and Detmar, 2016; Ulvmar and Mäkinen, 2016; Potente and Mäkinen, 2017). In this review, we aim to summarize the latest results and their significance in under-