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WIREs Dev Biol
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Building the drains: the lymphatic vasculature in health and disease

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The lymphatic vasculature is comprised of a network of endothelial vessels found in close proximity to but separated from the blood vasculature. An essential tissue component of all vertebrates, lymphatics are responsible for the maintenance of fluid homeostasis, dissemination of immune cells, and lipid reabsorption under healthy conditions. When lymphatic vessels are impaired due to invasive surgery, genetic disorders, or parasitic infections, severe fluid build‐up accumulates in the affected tissues causing a condition known as lymphedema. Malignant tumors can also directly activate lymphangiogenesis and use these vessels to promote the spread of metastatic cells. Although their first description goes back to the times of Hippocrates, with subsequent anatomical characterization at the beginning of the 20th‐century, the lack of identifying molecular markers and tools to visualize these translucent vessels meant that investigation of lymphatic vessels fell well behind research of blood vessels. However, after years under the shadow of the blood vasculature, recent advances in imaging technologies and new genetic and molecular tools have accelerated the pace of research on lymphatic vessel development. These new tools have facilitated both work in classical mammalian models and the emergence of new powerful vertebrate models like zebrafish, quickly driving the field of lymphatic development back into the spotlight. In this review, we summarize the highlights of recent research on the development and function of the lymphatic vascular network in health and disease. WIREs Dev Biol 2016, 5:689–710. doi: 10.1002/wdev.246 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Signaling Pathways > Cell Fate Signaling Vertebrate Organogenesis > Musculoskeletal and Vascular
Stepwise Model for Lymphatic Endothelial Cell Specification and Differentiation. (a) Lymphatic endothelium emerges from ‘competent’ venous endothelium expressing Sox18 and Lyve1. Polarized expression of Prox1 on a subset of venous endothelial cells ‘biases’ these cells towards producing lymphatic endothelium and induces or allows continued maintenance of the expression of a number of different LEC genes including VEGFR3, the receptor for the lymphangiogenic factor VEGFC. (Reprinted with permission from Ref . Copyright 2014, Elsevier)
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Morphological characteristics of the lymphatic vasculature. (a) An overview of the human lymphatic system including lymphatic vessels, lymph nodes, and lymphoid tissue. Major veins into which the lymphatics drain are shown in blue. (b) The lymphatic endothelial cells attach directly to the extracellular matrix and surrounding cells via anchoring filaments (red). Valves (blue) prevent lymph reflux to promote unidirectional lymph propulsion (Green arrows). Note the extensive overlap of adjacent endothelial cells in lymphatic capillaries. (c) Surface view of a lymphatic capillary emphasizing the loose, button‐like intercellular junctions (blue) (Reprinted with permission from Ref . Copyright 2009 PMC). (d) Infant patient displaying severe primary lymphedema in lower limbs. Photo courtesy of Dr. Alejandro Venero Mortola from Lima, Peru.
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Trunk lymphatic vessel development in the zebrafish. Stage I: Lymphatic endothelial progenitor cells emerge from the posterior cardinal vein (PCV) and migrate dorsally along somite boundaries. Stage II: Lymphatic endothelial progenitors turn laterally at the level of the horizontal myoseptum (HM), growing toward the surface of the animal and then branching rostrally and caudally to form the parachordal line (PAC). Stage III: Lymphatic progenitors migrate dorsally and ventrally from the PAC specifically along arterial intersegmental vessels (aISV), not venous intersegmental vessels (vISV) to form the intersegmental lymphatic vessels (ISLV). Stage IV: Lymphatic endothelial cells that migrate ventrally stop just ventral to the dorsal aorta, turn and migrate rostrally, and caudally to form the thoracic duct (TD). Similarly, the lymphatic endothelial cells that migrate dorsally form the dorsal longitudinal lymphatic vessel along the dorsal longitudinal anastomotic vessels (DLAV). (a, c, e, and h) Diagrams illustrating the key stages of trunk lymphatic network assembly (green, developing lymphatics; red arrows, their growth direction) (Figure panels a,c,e,h were reprinted with permission from Ref Copyright 2014 ELSEVIER). (b, d, f, g, and i) To the right of each diagram are confocal images of the vasculature in fli1a:eGFP animals that correspond to each stage. In (b, d, and g) the developing lymphatic progenitors are colored green, and the blood vasculature is grey (Figure panels b,d,f,g,i were reprinted with permission from Ref . Copyright 2012 Cell Press). (i) Color‐coded image distinguishing the blood and lymphatic vasculature in the ventral half of the trunk at stage 4 (posterior cardinal vein and venous intersegmental vessel, blue; dorsal aorta and arterial intersegmental vessel, red; intersegmental lymphatic vessel and the developing thoracic duct, green). (j) Anatomy of the zebrafish trunk and its vasculature at ~3 days post fertilization showing the location of the parachordal line (PAC) (Figure panel (j) was reprinted with permission from Ref . Copyright 2003 The Company of Biologists Ltd). Vessels are shown relative to adjacent structures in the mid‐trunk including the gut (G), myotomes (M), notochord (N), neural tube (NT), left pronephric duct (P), and yolk mass (Y). The parachordal lines (PAC) develop longitudinally to either side of the notochord, along the horizontal myoseptum and close to the lateral surfaces of the trunk. Anterior is towards the left and above the plane of the page, and dorsal is upwards.
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Functional characterization of zebrafish lymphatic vessels. (a) Methods used to image blood or lymphatic vessels. The red box on the fish drawing shows the approximate region of the trunk imaged in panels (b), (c), (d), (e), and (f). The blue box on the drawing shows the approximate region of the trunk imaged in panel (f and g). (b) Angiography of a 14 dpf Tg(fli1:EGFP)yl zebrafish (green) injected with fluorescent microspheres (red), labeling dorsal aorta (large arrow) and posterior cardinal vein (asterisk) but not lymphatic thoracic duct (small arrow). (c) Lymphangiography of 3 week Tg(fli1:EGFP)yl zebrafish (green) injected with fluorescent microspheres (red), labeling thoracic duct (small arrow) but not dorsal aorta (large arrow). (d) Time‐averaged confocal image of a 7 dpf Tg(fli1:EGFP)yl (green) and Tg(gata1:dsRed) (red) double transgenic animal, showing red fluorescence in the dorsal aorta (large arrow) and cardinal vein (asterisk) but not lymphatic thoracic duct (small arrow). (e–g) Confocal imaging of an 18 dpf Tg(fli1:EGFP)yl zebrafish (green) injected subcutaneously with 2 Md rhodaminedextran (red). (e) Subcutaneously injected rhodamine‐dextran drains into the thoracic duct (small arrow) but does not label the adjacent dorsal aorta (large arrow). (f) Numerous rhodamine‐dextran labeled vessels (red) are visible between the blood vessels (green). (g) Higher magnification image of blind‐ended rhodamine‐dextran labeled vessels. Scale bars = 20 µm (e), 50 µm (b,c,d,g), 100 µm (f). Panels (a)–(g) were reprinted with permission from Ref . Copyright 2006 Nature Publishing Group. (h, i) Lateral view of a 5 dpf zebrafish embryo displaying the vascular and lymphatic vasculature in the double transgenic Tg(fli:EGFP)yl;Tg(lyve1:dsRed). (i) Higher magnification image of the white box from panel (h), where it is possible to distinguish the cardinal vein (CV), dorsal aorta (DA), and the lymphatic thoracic duct (TD).
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