Histochem Cell Biol (2008) 130:1063–1078 DOI 10.1007/s00418-008-0525-5 REVIEW Developmental and pathological lymphangiogenesis: from models to human disease Hélène Maby-El Hajjami · Tatiana V. Petrova Accepted: 2 October 2008 / Published online: 23 October 2008 © The Author(s) 2008. This article is published with open access at Springerlink.com Abstract The lymphatic vascular system, the body’s sec- Introduction ond vascular system present in vertebrates, has emerged in recent years as a crucial player in normal and pathological The complexity of the circulatory networks of animals processes. It participates in the maintenance of normal tends to increase as species increase in size. Apart from the tissue Xuid balance, the immune functions of cellular and cardiovascular system, vertebrates also possess a lymphatic antigen traYcking and absorption of fatty acids and lipid- system that consists of the lymphatic vessels and the lym- soluble vitamins in the gut. Recent scientiWc discoveries phoid organs such as lymph nodes, mucosal-associated have highlighted the role of lymphatic system in a number lymphoid tissue (MALT) (tonsils, Peyer’s patches, and of pathologic conditions, including lymphedema, inXam- lymphoid tissues associated to the bronchial and nasal sys- matory diseases, and tumor metastasis. Development of tems), spleen, and thymus. Blood and lymphatic vessels genetically modiWed animal models, identiWcation of lym- comprise two interdependent vascular networks in most tis- phatic endothelial speciWc markers and regulators coupled sues; however, their organization and function are distinct. with technological advances such as high-resolution imag- The cardiovascular system forms a continuous loop around ing and genome-wide approaches have been instrumental in which the heart pumps blood, whereas the lymphatic sys- understanding the major steps controling growth and tem comprises a one-way, open-ended transit network with- remodeling of lymphatic vessels. This review highlights the out a central driving force. Blood vessels deliver blood recent insights and developments in the Weld of lymphatic cells, nutrients, hormones, and oxygen to tissues, whereas vascular biology. lymphatic vasculature removes macromolecules, microbes, and other substances from interstitial space. Keywords Lymphangiogenesis · Lymphedema · The lymphatic system comprises a network of blind- Tumor metastasis · InXammation ended lymphatic capillaries (also called initial lymphatic vessels) that collect the excess extravasated tissue Xuid that has originated as capillary inWltration from the blood serum (Fig. 1). After being collected by the lymphatic capillaries, the lymph is transported through a system of lymphatic ves- sels of progressively larger size, to pre-collector lymphatic H. Maby-El Hajjami · T. V. Petrova (&) vessels (Sacchi et al. 1997) then larger collecting lymphatic Division of Experimental Oncology, vessels, which converge into lymphatic trunks, and the Centre Pluridisciplinaire d’Oncologie, lymph is Wnally returned to the venous circulation via a CHUV and University of Lausanne, Ch. des Boveresses 155, 1066 Epalinges, Switzerland connection with subclavian veins (Casley-Smith 1980; e-mail: [email protected] Moore 1985). Thus the main function of the lymphatic sys- tem is to maintain normal tissue Xuid balance by restoring T. V. Petrova interstitial Xuid to the cardiovascular system. In addition, in Molecular and Cancer Biology Research Program, University of Helsinki, Haartmaninkatu 8, the digestive tract, lacteal lymphatic vessels inside the P.O. Box 63, 00014 Helsinki, Finland intestinal villi absorb and transport fat-soluble vitamins 123 1064 Histochem Cell Biol (2008) 130:1063–1078 (Leak 1976). Endothelial cells of lymphatic capillaries are oak leaf shaped and are interconnected by specialized discontinuous button-like junctions, whereas collecting lymphatic vessels downstream have continuous zipper-like junctions found also in blood vessels (Baluk et al. 2007). Overlapping endothelial cell–cell contacts (also called pri- mary valves) in initial lymphatic vessels prevent Xuid escaping back into the interstitial space (Schmid-Schönbein 2003; Trzewik et al. 2001). Lymphatic capillary endothelial cells are closely linked to the surrounding extracellular matrix by elastic Wbers known as anchoring Wlaments (Gerli et al. 1991; Leak and Burke 1968), which prevent vessel collapse in conditions of high interstitial pressure, indeed in this condition the junctions of the initial lymphatics open and the anchoring Wlaments stretch, allowing Xuid to move into the vessel. Anchoring Wlaments are made of Wbrillin (Gerli et al. 2000; Solito et al. 1997), a large glycoprotein that contains an Arg–Gly–Asp (RGD) motif capable of binding v3 integrins, which are transmembrane glyco- proteins that cluster at focal adhesion plaques. Pre-collector Fig. 1 Organization of lymphatic vascular system. The lymph is col- lymphatic vessels are characterized by the alternation of lected by a network of blind-ended lymphatic capillaries and is trans- areas with the same structural simplicity as initial lym- ported by pre-collector lymphatic vessels and collecting lymphatic phatic capillaries and areas with a well-developed muscular vessels, which are emptied into veins in the jugular region. Lymphatic coat, but the ultrastructural features of these diVerent por- capillaries consist of thin-walled lymphatic endothelial cells with over- V W lapping junctions which look like valves. Anchoring Wlaments, con- tions do not di er, and anchoring laments are present in taining Wbrillin, connect lymphatic capillaries to the extracellular both (Scavelli et al. 2004). The pre-collecting lymphatic matrix and prevent vessel collapse during increased interstitial pres- vessels merge into collecting lymphatic vessels, and the two sure. The pre-collector and collecting lymphatic vessels have a base- types of vessels have a basement membrane, and are sur- ment membrane, are surrounded by smooth muscle cells (red) and contain intraluminal valves that prevent lymph blackXow rounded by SMCs with intrinsic contractile activity to pro- mote lymph Xow. The latter is also due to the contraction of surrounding skeletal muscles, as well as arterial pulsations. (A, D, E, and K) and dietary fat, released by enterocytes in Like veins, the larger lymphatic vessels contain one-way the form of lipid particles called chylomicrons. Further- intraluminal valves that aid in lymph propulsion by prevent- more, the lymphatic system is an important part of immune ing backXow (Leak and Burke 1966; von der Weid and surveillance by carrying antigens and antigen presenting Zawieja 2004). Compared to blood vessels, the lymphatic cells from the interstitium to be displayed for B and T cells vasculature is a low Xow and low pressure system. in the lymph nodes. In addition to these physiological tasks the lymphatic system plays a major role in a number of pathologic conditions, including lymphedema, inXamma- Development of lymphatic vasculature tory diseases, and tumor metastasis. Present in the skin and in most internal organs, with the Embryonic development concepts exception of avascular structures such as epidermis, hair, nails, cartilage, and cornea, and some vascularised organs The Wrst description of the lymphatic system dates back to such as the brain, bone marrow, and retina, the lymphatic the seventeenth century, when Gasparo Aselli identiWed vasculature is composed of vessels with distinct morpho- lymphatic vessels as ‘‘milky veins’’ in the mesentery of a logical features (Fig. 1). Similar to blood capillaries, lym- ‘‘well-fed’’ dog (Asellius 1627). However, the embryonic phatic capillaries consist of a single layer of thin-walled, origin of lymphatic vessels remained unclear for a long non-fenestrated lymphatic endothelial cells (LECs), but time until F. Sabin (1902, 1909) and F. Lewis (1905) postu- they diVer in that they are not ensheathed by pericytes or lated, at the beginning of the twentieth century, that LECs smooth muscle cells (SMCs), and have an absent or poorly are derived from the venous endothelium. This “centrifu- developed basement membrane. In addition, they lack tight gal” theory proposes that endothelial cells bud oV from the junctions and adherens junctions, which allow easy access veins during early embryonic development and form primi- for Xuid, macromolecules, and cells into the vessel lumen tive lymph sacs in the jugular region (reviewed by Oliver 123 Histochem Cell Biol (2008) 130:1063–1078 1065 2004). From these sacs, budding endothelial cells centrifu- corneal lymphangiogenesis (Maruyama et al. 2005; Religa gally sprout towards the periphery, forming capillaries that et al. 2005; Schledzewski et al. 2006). However, bone mar- surround tissues and organs. An alternative, “centripetal” row-derived progenitor cells did not incorporate signiW- theory, suggests that LECs are derived from mesenchymal cantly into the endothelium of newly formed lymphatic progenitor cells, which, nowadays, are called lymphangio- vessels in mouse tumor xenografts (He et al. 2004), and blasts (Huntington and Mc Clure 1910). Several recent more generally, a growing body of evidence suggest that studies in genetically engineered mouse models (Srinivasan circulating bone marrow-derived progenitor cells may pro- et al. 2007; Wigle et al. 2002; Wigle and Oliver 1999) and mote growth of vessels mainly by acting as supporting cells in vivo imaging of developing lymphatic vasculature in (Grunewald