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Reprint requests Address requests for reprints to: Yasuko Iwakiri, PhD, Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, TAC S223B, 333 Cedar Street, New Haven, Connecticut 06520. fax: (203) 785-7273.
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.
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.
Lymphatic vascular research was impeded by a lack of knowledge about the markers and signaling pathways specific to the lymphatic vasculature. From 1995 to 1997, however, it was shown that vascular endothelial growth factor receptor (VEGFR)-3 is expressed in the lymphatic endothelium and that its ligand vascular endothelial growth factor (VEGF)-C promotes lymphangiogenesis.
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),
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.
Structure of the Hepatic Lymphatic Vascular System
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.
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.
They are highly permeable, with discontinuous “button-like” junctions through which interstitial fluid, macromolecules, and immune cells can be transported.
An immunological correlation between the anchoring filaments of initial lymph vessels and the neighboring elastic fibers: a unified morphofunctional concept.
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.
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.
On the other hand, LyECs produce the vasodilator nitric oxide (NO) in response to shear stress from fluid flow, counteracting Ca2+-dependent contraction.
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.
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.
Lymphatic fluid that enters the subclavian veins returns to the systemic blood circulation.
Figure 1Schematic diagram of macro-anatomy of hepatic lymphatic vascular system. (1) Lymphatic capillaries in the portal tract coalesce into collecting vessels, which drain to lymph nodes at the hepatic hilum and the lesser omentum. Efferent lymphatic vessels (LV) from these lymph nodes connect to celiac lymph nodes, which drain to the cisterna chyli, the enlarged origin of the thoracic duct. Lymphatic fluid through the thoracic duct drains to the left subclavicular vein and returns to the systemic blood circulation. (2) Lymphatic vessels along the central vein (CV) converge into large lymphatic vessels along the hepatic vein (HV), which then traverse along the inferior vena cava (IVC) through the diaphragm toward mediastinal lymph nodes. (3) Lymphatic fluid running underneath the capsule of the convex surface of the liver (3i) drains to mediastinal lymph nodes through the coronary ligament, whereas that of the concave surface (3ii) drains to lymph nodes of the hepatic hilum and regional lymph nodes. BD, bile duct; HA, hepatic artery; LN, lymph node; PV, portal vein.
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.
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,
Figure 2Schematic diagram of the micro-anatomy of the hepatic lymphatic vascular system. Blood flow (red arrows) from the portal vein (PV) and hepatic artery (HA) enters the liver. Plasma components are filtered through LSECs into the space of Disse, the interstitial space between LSECs and hepatocytes, and are regarded as the source of lymphatic fluid. Lymphatic fluid in the space of Disse mostly flows through the space of Mall, the space between the stroma of the portal tract and the outermost hepatocytes, into the interstitium of the portal tract and then into lymphatic capillaries (1). Some portion of the lymphatic fluid in the space of Disse flows into the interstitium around the central vein (2) or underneath the hepatic capsule (3).
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. Lymphatic fluid running underneath the capsule of the convex surface of the liver drains to mediastinal lymph nodes through the coronary ligament, whereas that fluid running along the concave surface drains to lymph nodes in the hepatic hilum and to regional lymph nodes (Figure 1).
On the basis of their locations, lymphatic vessels along the portal tract and the central vein are called the deep lymphatic system, and those along the hepatic capsule are called the superficial lymphatic system.
Identification of more specific markers for the liver is needed because the most common LyEC markers, LYVE-1 and Prox1, are also expressed in LSECs and hepatocytes, respectively. Table 1 summarizes LyEC markers histologically examined in the liver.
Table 1Lymphatic Markers
Marker
Postnatal expression except for lymphatic vessels
Hepatic expression in pathologic conditions
Reference
Liver
Other organs/cells
LYVE-1
Sinusoidal endothelial cells
A portion of macrophages, pulmonary capillaries, epididymal adipose tissue, mesentery, eye (cornea, sclera, choroid, iris, and retina), wounded skin, and malignant tumors (melanoma and insulinoma)
In chronic hepatitis and liver cirrhosis in humans, LYVE-1(+) lymphatic vessels increase, but LYVE-1(+) sinusoidal endothelial cells decrease.
Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+, F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis.
Podoplanin(+) lymphatic vessels increase in decompensated cirrhosis in humans. Podoplanin(+) FRCs increase in livers of primary biliary cirrhosis patients. EHE and angiomyolipoma in humans.
Detailed analysis of intrahepatic CD8 T cells in the normal and hepatitis C-infected liver reveals differences in specific populations of memory cells with distinct homing phenotypes.
Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease.
Mannose receptor and its putative ligands in normal murine lymphoid and nonlymphoid organs: in situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular microglia, and mesangial cells, but not dendritic cells.
Its structural features suggest that LYVE-1 may be involved in the transport of HA across the lymphatic endothelium. LYVE-1 is strongly expressed on the entire luminal and abluminal surfaces of LyECs, even on the fine filopodia of growing vessels during lymphangiogenesis.
No definite alterations in lymphatic vessel structure and function were reported for LYVE-1–/– mice.
However, diphtheria toxin-induced LYVE-1 depletion in mice caused acute loss of lymphatic lacteals in intestinal villi and lymphatic vessels in systemic lymph nodes. These changes resulted in the structural distortion of blood capillaries and villi, leading to death due to sepsis within 60 hours after LYVE-1 depletion.
These observations indicate that LYVE-1 plays an important role in the maintenance of the lymphatic vascular system, especially lacteals in intestinal villi and lymph nodes. Compensatory mechanisms in the setting of congenital loss of LYVE-1 may explain the relatively mild phenotype of these mice.
In the liver, LYVE-1 is expressed not only in LyECs but also in LSECs, as shown in mice
Prox1, a homolog of the Drosophila melanogaster homeobox gene prospero, is a transcription factor and regulates genes related to LyECs, including VEGFR-3 and podoplanin.
; Prox1–/– mice lack a lymphatic vascular system and die at approximately E14.5. Prox1 heterozygote mice die a few days after their birth and demonstrate dysfunction of lymphatic vessels with chylous ascites.
In humans, cholangiocytes of normal livers were negative for Prox1 expression, but intrahepatic cholangiocarcinoma and ductular cells in fibrotic septa of cirrhotic livers and HCC were positive.
A Prospero-related homeodomain protein is a novel co-regulator of hepatocyte nuclear factor 4alpha that regulates the cholesterol 7alpha-hydroxylase gene.
Prospero-related homeobox (Prox1) is a corepressor of human liver receptor homolog-1 and suppresses the transcription of the cholesterol 7-alpha-hydroxylase gene.
Prospero-related homeobox 1 (Prox1) functions as a novel modulator of retinoic acid-related orphan receptors alpha- and gamma-mediated transactivation.
Prospero-related homeobox (Prox1) is a corepressor of human liver receptor homolog-1 and suppresses the transcription of the cholesterol 7-alpha-hydroxylase gene.
Prospero-related homeobox 1 (Prox1) functions as a novel modulator of retinoic acid-related orphan receptors alpha- and gamma-mediated transactivation.
Podoplanin is also a ligand of C-type lectin receptor CLEC-2, which is highly expressed in platelets and immune cells and promotes platelet aggregation and activation.
Podoplanin–/– mice die at birth as a result of respiratory failure. These mice have congenital lymphedema caused by lymphatic vessel defects, although blood vessel formation is normal.
Podoplanin has proven to be a useful histologic marker for diagnosing patients who have vascular tumors with lymphatic differentiation, such as epithelioid hemangioendotheliomas (EHEs)
VEGFR-3 is a membrane-anchored tyrosine kinase and the receptor for VEGF-C and VEGF-D. It plays a crucial role in lymphangiogenesis. In early embryogenesis before LyEC differentiation, VEGFR-3 is expressed in most endothelial cells, but in the later stages of development, its expression becomes mostly restricted to the lymphatic endothelium.
A mouse line (Vegfr3EGFPLuc) in which a dual reporter for fluorescence and luminescence is expressed under VEGFR-3-promoter was established recently, enabling luminescence imaging of tumor-induced lymphangiogenesis.
Hepatitis B x antigen (HBx Ag), one of the antigens of hepatitis B virus, promotes hepatocarcinogenesis by upregulating expression of genes associated with proliferation of hepatocytes; upregulation of VEGFR-3 expression was observed in HBx Ag–positive human HCC, and the prognosis of patients with VEGFR-3–positive HCC was worse than for those with VEGFR-3–negative HCC.
This section addresses the mechanism of lymphangiogenesis in the postnatal stage and factors that affect lymphangiogenesis, including inflammatory cells, in the lymphatic system in general and then summarizes the implications of lymphangiogenesis in the pathophysiology of liver diseases.
Factors Associated With Lymphangiogenesis
In the postnatal stage, lymphatic vessels are mostly quiescent, and lymphangiogenesis generally occurs in pathologic conditions such as tissue repair, inflammation, and tumor-related conditions.
Many cytokines and growth factors have been reported to promote lymphangiogenesis or inhibit lymphangiogenesis, as summarized in Table 2. The extent and duration of lymphangiogenesis are determined by the balance between pro- and anti- lymphangiogenic factors.
Ang 2 is expressed in lymphatic vessels and macrophages in inflamed cornea. Inflammatory lymphangiogenesis of cornea is suppressed in Ang2 knockout mice. Ang2 blockade inhibits LyEC proliferation and capillary tube formation.
Human dermal lymphatic microvascular endothelial cells
TGF-β inhibits LyEC proliferation, cord formation, migration, expression of lymphatic markers (LYVE-1, Prox1), and lymphangiogenesis by VEGF-A/C via TGF-β type I receptor.
Mouse LyEC isolated from LNs, human dermal LyEC, mouse asthma model
IL4 and IL13 inhibit expression of Prox1 and LYVE-1 and tube formation of LyEC. Blockade of IL4 and/or IL13 increases the density and function of lung LVs in asthma model.
Intracellular Signaling Pathways in Lymphangiogenesis
Signaling pathways in lymphangiogenesis have largely been determined in studies of developmental lymphangiogenesis. Signaling via VEGF-C/D and VEGFR-3 is the most well-known pathway for lymphangiogenesis (Figure 3).
Chronic inflammation and malignant tumors in the liver induce several pro-lymphangiogenic growth factors including VEGF-C/D. However, a direct link between these increased pro-lymphangiogenic growth factors and lymphangiogenesis in these pathologic conditions remains to be demonstrated (Figure 3). Excellent review articles are available detailing signaling pathways in lymphangiogenesis.
Figure 3Intracellular signaling pathways in lymphangiogenesis. Signaling via VEGF-C/D and VEGFR-3 is the most well-known pathway for lymphangiogenesis. VEGF-C or VEGF-D binds to its receptor VEGFR-3 in the plasma membrane of LyECs, which facilitates signal transduction through various intracellular signaling pathways, leading to lymphangiogenesis. In the liver, activated macrophages in chronic inflammatory conditions, such as chronic hepatitis and liver cirrhosis, secrete VEGF-C and/or VEGF-D. Malignant liver tumors, such as HCC and intrahepatic cholangiocarcinoma, also secrete VEGF-C and/or VEGF-D. Furthermore, these malignant tumors activate tumor-associated macrophages, which also secrete VEGF-C and/or VEGF-D. Secreted VEGF-C and VEGF-D are likely related to lymphangiogenesis in liver diseases through VEGFR-3–mediated pathways.
Adaptive immune responses are initiated by the migration of immune cells to inflamed sites where they phagocytose pathogens and transmigrate through lymphatic vessels to lymph nodes to present antigens to T cells. However, immune cells not only migrate through lymphatic vessels but also interact with lymphatic vessels and promote lymphangiogenesis.
Among the various immune cells, macrophages interact most with lymphatic vessels. LyECs secrete chemotactic factors, such as C10, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1, to attract macrophages.
However, this is controversial and requires further investigation.
Dendritic cells
Upregulation of inflammatory cytokines such as tumor necrosis factor-α and interleukin (IL) 1β in inflamed tissues promotes expression of chemokines (eg, CCL21/CCL19 and CXCL12) and their receptors (eg, CCR7 and CXCR-4) in LyECs and dendritic cells,
Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes.
Inflammatory cytokines also increase expression of adhesion molecules such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin in LyECs and promote dendritic cell transmigration to lymphatic vessels.
In a mouse model of tail lymphedema, nude mice exhibited less edema than wild-type mice, concomitant with decreased lymphangiogenic cytokines and increased anti-lymphangiogenic cytokines. The balance between these cytokines was modulated by T-cell–mediated inflammation.
B cells promote lymphangiogenesis in inflamed lymph nodes by secreting a robust amount of VEGF-A in mice given keyhole-limpet hemocyanin emulsified in complete Freund’s adjuvant (an experimental model of inflamed lymph nodes).
Interestingly, VEGF-C was not detected in this study. Another study that used transgenic mice overexpressing VEGF-A specifically in B cells showed increased lymphangiogenesis as well as angiogenesis.
The bioavailability of VEGF-A is increased by the secretion of matrix metalloproteinases 9 and heparanase. Depletion of neutrophils in mice resulted in skin inflammation in response to immunization or contact hypersensitization, and lymphangiogenesis was decreased in these mice with increased local inflammation, suggesting that neutrophils play a role in lymphangiogenesis and that lymphangiogenesis is helpful for reducing inflammation.
Lymphangiogenesis in the Liver
Because 25%–50% of lymph passing through the thoracic duct originates in the liver,
the liver can be considered the most important organ for lymphatic fluid production. However, the lymphatic vascular system in the liver has been minimally explored. A small number of studies have reported on hepatic lymphangiogenesis in pathologic conditions such as chronic hepatitis, liver fibrosis/cirrhosis, portal hypertension, malignant tumors, and post-transplantation. This section summarizes these studies.
Chronic hepatitis, liver fibrosis, and cirrhosis
Resistance to sinusoidal blood flow increases in cirrhotic livers because of architectural deformations including around the portal and central venules. Consequently, sinusoidal hydrostatic pressure is elevated, and plasma components filtrated through sinusoids (which form lymphatic fluid) increase. In cirrhotic patients, lymphatic fluid produced in the liver increases up to 30-fold,
Ascites formation in association with cirrhosis is one of the most recognized clinical manifestations of lymphatic vascular disorders. How ascites is formed still remains to be elucidated. Although several theories have been put forward,
Effective plasma volume in cirrhosis with ascites: evidence that a decreased value does not account for renal sodium retention, a spontaneous reduction in glomerular filtration rate (GFR), and a fall in GFR during drug-induced diuresis.
According to this theory, splanchnic arterial vasodilation caused by portal hypertension results in underfilling of the splanchnic arterial circulation (hypovolemia). In moderate stages, the hypovolemia is compensated for by renal retention of sodium and water. However, in severe portal hypertension with splanchnic arterial vasodilation, sodium and water retention is persistent and leads to leakage of fluid into the peritoneal cavity. When its amount exceeds the absorption capacity of lymphatic vessels, ascites results.
On a related note, impaired lymphatic drainage in the splanchnic and peripheral regions was reported in cirrhotic rats with ascites. This was accompanied by increased activity of endothelial NO synthase and production of NO by LyECs in these regions.
In addition, smooth muscle cell coverage of lymphatic vessels in these regions was significantly decreased. Treatment of these cirrhotic rats with an NO synthase inhibitor improved lymphatic drainage, decreased ascites volume, and increased smooth muscle cell coverage. This study thus demonstrates a role for NO in the impairment of lymphatic vessels in splanchnic and peripheral regions and in the development of ascites. It is not known whether lymphatic vessels in human cirrhotic livers show similar pathologic features.
The occurrence of hepatic lymphangiogenesis was reported for the first time in liver fibrosis and cirrhosis by Vollmar et al
in 1997. They found lymphatic vessels to be increased and enlarged in rat liver cirrhosis induced by carbon tetrachloride (CCl4). These observations were confirmed the following year in patients with chronic viral hepatitis/cirrhosis.
Microarray analysis demonstrated a 4-fold increase in VEGF-D expression in endothelial cells from CCl4-induced cirrhotic rat livers as compared with control rat livers. Because VEGF-D is a well-known lymphangiogenic factor that binds to VEGFR-3,
It was presumed that increased lymph production that was due to increased portal pressure caused lymphangiogenesis. In 2 rat models of portal hypertension (portacaval shunt and portal vein ligation), upregulation of Vegfr-3 expression was observed, leading us to speculate the occurrence of lymphangiogenesis.
Hepatic proliferation and angiogenesis markers are increased after portal deprivation in rats: a study of molecular, histological and radiological changes.
However, the significance and mechanism of hepatic lymphangiogenesis, including in chronic hepatitis and liver fibrosis and cirrhosis, remain unknown.
Malignant tumors
Lymphatic vessels play a pivotal role in the pathogenesis of malignant tumors by serving as a pathway through which tumor cells metastasize. The incidence of lymph node metastasis differs among tumors. For example, it is 5.1% in HCC and 45.1% in intrahepatic cholangiocarcinoma. The prognosis of tumor-bearing patients with lymph node metastasis is worse than in cases without such metastasis.
Many malignant tumors secrete lymphangiogenic factors such as VEGF-C and VEGF-D and promote lymphangiogenesis in their adjacent tissues, which helps tumor cells to metastasize to lymph nodes,
and many studies have demonstrated that tumor-associated macrophages play a vital role in lymphangiogenesis in malignant tumors by secreting VEGF-C and VEGF-D.
In intrahepatic cholangiocarcinoma, the lymphatic vessel density of surgically resected tumors was positively correlated with the incidence of lymphatic metastasis.
In HCC, VEGF-C expression was positively correlated with the size of tumors and the number of extrahepatic metastases and was negatively correlated with disease-free survival time.
Thus, blockade of VEGF-C may be a potential therapeutic strategy against malignant tumors. A VEGF-C neutralizing antibody (VGX-100) is now the subject of a Phase I clinical trial for adult patients with advanced or metastatic solid tumors (NCT01514123).
In solid organ transplants, lymphatic vessel connections between the graft and the recipient are interrupted. Because lymphatic vessels are essential for adaptive immunity, the association between lymphangiogenesis and graft rejection has received considerable attention. Post-transplant lymphangiogenesis in grafts was associated with acute cellular graft rejection in transplants of various organs (kidney,
Post-transplant lymphangiogenesis could be detrimental if newly formed lymphatic vessels promote antigen presentation in draining lymph nodes and provoke alloimmune responses that result in graft rejection. On the other hand, these newly formed lymphatic vessels could be beneficial if they efficiently clear immune cells. In a rat model of liver transplantation, post-transplant lymphangiogenesis in grafts was associated with long-term survival of recipients for more than 90 days.
In addition, rats that had failed grafting by 11 days with acute cellular rejection and antibody-mediated rejection showed disappearance of lymphatic vessels from severely rejected areas, suggesting that lymphatic vessels have an important role in mitigation of inflammation at least in the early stage of transplantation. Further investigations to determine the mechanism and the time course of clearance of infiltrating immune cells by lymphatic vessels, especially in the early post-transplant period, may help increase transplant success.
Conclusions and Perspective
The lymphatic vascular system has been poorly studied in the liver. To drive research in this area, it is essential to identify better markers for LyECs that do not overlap with markers for LSECs, hepatocytes, and other liver cells. The development of experimental models for studying the lymphatic vascular system in postnatal livers will be important in examining its role and molecular mechanisms in physiological and pathophysiological conditions. Although this field is wide open, it may be helpful to identify specific questions particularly in need of study.
First, the mechanism of hepatic lymphangiogenesis is largely unknown. The VEGF-C/VEGFR-3 axis is considered the most potent signaling pathway that regulates lymphangiogenesis in other organs.
However, cellular sources of VEGF-C and VEGFR-3 have not been fully identified in the liver. Furthermore, as shown in Table 2, many other molecules are reported to regulate lymphangiogenesis. These molecules are mostly observed in the liver in physiological and pathophysiological conditions. It would be worth characterizing these molecules in relation to hepatic lymphangiogenesis.
Second, although the relationship between the lymphatic vascular system and metastasis is well-known and the growth of lymphatic capillaries in liver tumors has been observed, the role of lymphatic capillary growth in the development and progression of liver tumors is largely unknown. As for angiogenesis, it would be interesting to investigate lymphangiogenesis in liver cancer.
Third, inflammation is closely related to the development of many liver diseases, and infiltrating immune cells are drained to lymphatic vessels. Thus, it would be interesting to examine lymphangiogenesis in relation to inflammation in the liver. It is also unknown how immune cells recognize lymphatic vessels at the time of migration. Elucidation of these mechanisms may help in the development of anti-inflammatory strategies that facilitate immune cell clearance.
Fourth, although LyECs are derived from cardinal veins
VAP-1, a type II transmembrane protein that supports leukocyte adhesion, and reelin, a glycoprotein that is associated with embryonic development, are also expressed in both LyECs and LSECs.
Furthermore, under normal conditions, neither LyECs nor LSECs are associated with basement membranes. Examining the similarities and differences between these 2 types of endothelial cells could help to understand endothelial cell–related liver function.
In summary, the lymphatic vascular system in the liver is a large open area for investigation.
More research will significantly advance our understanding of liver physiology and pathophysiology and in turn contribute to the development of new therapeutic strategies for many liver diseases.
Acknowledgments
The authors thank Dr Teruo Utsumi for his careful review of the manuscript and helpful suggestions.
References
Chung C.
Iwakiri Y.
The lymphatic vascular system in liver diseases: its role in ascites formation.
An immunological correlation between the anchoring filaments of initial lymph vessels and the neighboring elastic fibers: a unified morphofunctional concept.
A Prospero-related homeodomain protein is a novel co-regulator of hepatocyte nuclear factor 4alpha that regulates the cholesterol 7alpha-hydroxylase gene.
Prospero-related homeobox (Prox1) is a corepressor of human liver receptor homolog-1 and suppresses the transcription of the cholesterol 7-alpha-hydroxylase gene.
Prospero-related homeobox 1 (Prox1) functions as a novel modulator of retinoic acid-related orphan receptors alpha- and gamma-mediated transactivation.
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