The Hepatic Lymphatic Vascular System: Structure, Function, Markers, and Lymphangiogenesis

The lymphatic vascular system has been minimally explored in the liver despite its essential functions including maintenance of tissue fluid homeostasis. The discovery of specific markers for lymphatic endothelial cells has advanced the study of lymphatics by methods including imaging, cell isolation, and transgenic animal models and has resulted in rapid progress in lymphatic vascular research during the last decade. These studies have yielded concrete evidence that lymphatic vessel dysfunction plays an important role in the pathogenesis of many diseases. This article reviews the current knowledge of the structure, function, and markers of the hepatic lymphatic vascular system as well as factors associated with hepatic lymphangiogenesis and compares liver lymphatics with those in other tissues. The lymphatic vascular system has been minimally explored in the liver despite its essential functions including maintenance of tissue fluid homeostasis. The discovery of specific markers for lymphatic endothelial cells has advanced the study of lymphatics by methods including imaging, cell isolation, and transgenic animal models and has resulted in rapid progress in lymphatic vascular research during the last decade. These studies have yielded concrete evidence that lymphatic vessel dysfunction plays an important role in the pathogenesis of many diseases. This article reviews the current knowledge of the structure, function, and markers of the hepatic lymphatic vascular system as well as factors associated with hepatic lymphangiogenesis and compares liver lymphatics with those in other tissues. SummaryResearch on the lymphatic vascular system has advanced rapidly during the last decade, and lymphatic dysfunction is now implicated in the pathogenesis of multiple diseases. This review provides an overview of the lymphatic vascular system in the liver. Research on the lymphatic vascular system has advanced rapidly during the last decade, and lymphatic dysfunction is now implicated in the pathogenesis of multiple diseases. This review provides an overview of the lymphatic vascular system in the liver. The lymphatic and blood vascular systems together constitute the circulatory system, and both have essential physiological activities. The lymphatic vascular system maintains tissue fluid homeostasis by collecting excess tissue fluid and returning it to the venous circulation. It also plays an essential role in the absorption and transport of dietary fat. Furthermore, lymphatics serve as the main conduits of antigens and antigen-presenting cells from the periphery to lymph nodes and are thus crucial for immune surveillance and acquired immunity.1Chung C. Iwakiri Y. The lymphatic vascular system in liver diseases: its role in ascites formation.Clin Mol Hepatol. 2013; 19: 99-104Crossref PubMed Google Scholar, 2Tammela T. Alitalo K. 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Mustonen T. et al.Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development.Proc Natl Acad Sci U S A. 1995; 92: 3566-3570Crossref PubMed Google Scholar, 6Jeltsch M. Kaipainen A. Joukov V. et al.Hyperplasia of lymphatic vessels in VEGF-C transgenic mice.Science (New York, NY). 1997; 276: 1423-1425Crossref Scopus (931) Google Scholar This finding identifying signaling pathways specific to the lymphatic vasculature and subsequent discoveries of other specific markers for lymphatic endothelial cells (LyECs), such as lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1),7Banerji S. Ni J. Wang S.X. et al.LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan.J Cell Biol. 1999; 144: 789-801Crossref PubMed Scopus (588) Google Scholar prospero homeobox protein 1 (Prox1),8Wigle J.T. Oliver G. Prox1 function is required for the development of the murine lymphatic system.Cell. 1999; 98: 769-778Abstract Full Text Full Text PDF PubMed Scopus (877) Google Scholar and podoplanin,9Breiteneder-Geleff S. Soleiman A. Kowalski H. et al.Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium.Am J Pathol. 1999; 154: 385-394Abstract Full Text Full Text PDF PubMed Google Scholar significantly advanced lymphatic vascular research. As a consequence, it is now recognized that lymphatic vessel dysfunction plays an important role in the pathogenesis of various diseases. However, in the liver, the lymphatic vascular system has been little explored. This review will provide an overview of the structure, function, and markers of the lymphatic vascular system as well as factors associated with lymphangiogenesis in the liver, highlighting both new findings and areas needing further study. This section will address the structure of the lymphatic vascular system in general, followed by structural features specific to the liver. A detailed description of the anatomic structure of the lymphatic and hepatic lymphatic vascular systems is available in other review articles.3Schulte-Merker S. Sabine A. Petrova T.V. Lymphatic vascular morphogenesis in development, physiology, and disease.J Cell Biol. 2011; 193: 607-618Crossref PubMed Scopus (133) Google Scholar, 10Trutmann M. Sasse D. The lymphatics of the liver.Anat Embryol (Berl). 1994; 190: 201-209Crossref PubMed Google Scholar, 11Ohtani O. Ohtani Y. Lymph circulation in the liver.Anat Rec. 2008; 291: 643-652Crossref Scopus (40) Google Scholar, 12Pupulim L.F. Vilgrain V. Ronot M. et al.Hepatic lymphatics: anatomy and related diseases.Abdom Imaging. 2015; 40: 1997-2011Crossref PubMed Scopus (3) Google Scholar Lymphatic fluid originates from plasma components leaked from blood capillaries into the interstitium and then enters lymphatic capillaries, which are blind-ended, thin-walled vessels consisting of a single layer of LyECs. Lymphatic capillaries are not covered by pericytes or smooth muscle cells and lack basement membranes.13Alitalo K. Tammela T. Petrova T.V. Lymphangiogenesis in development and human disease.Nature. 2005; 438: 946-953Crossref PubMed Scopus (385) Google Scholar, 14Maby-El Hajjami H. Petrova T.V. Developmental and pathological lymphangiogenesis: from models to human disease.Histochem Cell Biol. 2008; 130: 1063-1078Crossref PubMed Scopus (51) Google Scholar They are highly permeable, with discontinuous “button-like” junctions through which interstitial fluid, macromolecules, and immune cells can be transported.15Baluk P. Fuxe J. Hashizume H. et al.Functionally specialized junctions between endothelial cells of lymphatic vessels.J Exp Med. 2007; 204: 2349-2362Crossref PubMed Scopus (186) Google Scholar LyECs have anchoring filaments that are mainly composed of emilin-1 and fibrillin and bind LyECs to the surrounding extracellular matrix.14Maby-El Hajjami H. Petrova T.V. Developmental and pathological lymphangiogenesis: from models to human disease.Histochem Cell Biol. 2008; 130: 1063-1078Crossref PubMed Scopus (51) Google Scholar, 16Danussi C. Spessotto P. Petrucco A. et al.Emilin1 deficiency causes structural and functional defects of lymphatic vasculature.Mol Cell Biol. 2008; 28: 4026-4039Crossref PubMed Scopus (57) Google Scholar, 17Solito R. Alessandrini C. Fruschelli M. et al.An immunological correlation between the anchoring filaments of initial lymph vessels and the neighboring elastic fibers: a unified morphofunctional concept.Lymphology. 1997; 30: 194-202PubMed Google Scholar These filaments keep lymphatic vessel lumens open, facilitating fluid intake in conditions of tissue swelling. Lymphatic capillaries coalesce into collecting vessels, which are covered with smooth muscle cells and have basement membranes.14Maby-El Hajjami H. Petrova T.V. Developmental and pathological lymphangiogenesis: from models to human disease.Histochem Cell Biol. 2008; 130: 1063-1078Crossref PubMed Scopus (51) Google Scholar Collecting vessels lack the discontinuous junctions typical of lymphatic capillaries and are thus much less permeable. Collecting vessels can be divided into smaller functional units called lymphangions that have unidirectional bicuspid valves at each end.18Breslin J.W. Mechanical forces and lymphatic transport.Microvasc Res. 2014; 96: 46-54Crossref PubMed Scopus (11) Google Scholar The phasic contraction of smooth muscle cells covering lymphangions enables collecting vessels to act as pumps to drive lymphatic flow. Stimulation of smooth muscle cells causes depolarization of cell membrane and opens Ca2+ channels, resulting in Ca2+ influx and smooth muscle cell contraction. Smooth muscle cells also have stretch-activated Ca2+ channels that facilitate phasic contraction.19Shirasawa Y. Benoit J.N. Stretch-induced calcium sensitization of rat lymphatic smooth muscle.Am J Physiol Heart Circ Physiol. 2003; 285: H2573-H2577Crossref PubMed Google Scholar, 20Davis M.J. Scallan J.P. 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Liao S. et al.Mechanobiological oscillators control lymph flow.Proc Natl Acad Sci U S A. 2015; 112: 10938-10943Crossref PubMed Scopus (0) Google Scholar Collecting vessels connect to 1 or more lymph nodes. Antigen-presenting cells including dendritic cells and macrophages in lymphatic fluid interact with lymphocytes in lymph nodes, facilitating adaptive immune responses. After reaching primary lymph nodes, lymphatic fluid flows to secondary central lymph nodes, tertiary central lymph nodes, and finally lymph trunks.24Forster R. Braun A. Worbs T. Lymph node homing of T cells and dendritic cells via afferent lymphatics.Trends Immunol. 2012; 33: 271-280Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Lymphatic fluid from the left side of the body, abdomen, and lower limb ultimately drains into the thoracic duct, the largest lymphatic vessel, which is connected to the left subclavian vein (Figure 1), whereas lymphatic fluid from other parts of the body drains into the right lymph trunk, which is connected to the right subclavian vein.25Jeltsch M. Tammela T. Alitalo K. et al.Genesis and pathogenesis of lymphatic vessels.Cell Tissue Res. 2003; 314: 69-84Crossref PubMed Scopus (62) Google Scholar Lymphatic fluid that enters the subclavian veins returns to the systemic blood circulation. A schematic diagram of the hepatic lymphatic system is shown in Figures 1 and 2. Unlike other tissues, the liver has sinusoids instead of capillaries.26Wake K. Sato T. “The sinusoid” in the liver: lessons learned from the original definition by Charles Sedgwick Minot (1900).Anat Rec (Hoboken). 2015; 298: 2071-2080Crossref PubMed Google Scholar Sinusoids, similar to lymphatic capillaries, are distinct from blood capillaries in that they consist of 1 layer of liver sinusoidal endothelial cells (LSECs) and lack basement membranes. Hepatic lymphatic fluid is thought to originate from plasma components filtered through the fenestrae of LSECs into the space of Disse, the interstitial space between LSECs and hepatocytes.10Trutmann M. Sasse D. The lymphatics of the liver.Anat Embryol (Berl). 1994; 190: 201-209Crossref PubMed Google Scholar, 11Ohtani O. Ohtani Y. Lymph circulation in the liver.Anat Rec. 2008; 291: 643-652Crossref Scopus (40) Google Scholar Fluid in the space of Disse primarily flows through the space of Mall, a space between the stroma of the portal tract and the outermost hepatocytes,27Mall F.P. A study of the structural unit of the liver.American Journal of Anatomy. 1906; 5: 227-308Crossref Google Scholar into the interstitium of the portal tract and then into lymphatic capillaries. Some portion of the fluid in the space of Disse flows into the interstitium around the central vein, which is located in the center of the liver acinus and connected to the hepatic vein,28Munoz S.J. Fenkel J.M. Kiley K. The liver in circulatory failure.in: Schiff E.R. Maddrey W.C. Sorrell M.F. Schiff's diseases of the liver. Wiley-Blackwell, Hoboken2011: 924-933Crossref Google Scholar or underneath the hepatic capsule (Figure 2). Lymphatic capillaries in the portal tract coalesce into collecting vessels and drain to lymph nodes at the hepatic hilum, whereas lymphatic vessels along the central vein converge into 5–6 large lymphatic vessels that traverse along the inferior vena cava through the diaphragm toward posterior mediastinal lymph nodes. 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