Lymphatic Endothelial Heparan Sulfate In Dendritic Cell Trafficking
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Lymphatic Endothelium
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The lymphatic system plays a key role in tissue homeostasis, fatty acid transport, and immune surveillance. Pathologically, dysfunction of the lymphatic system results in edema, and increased lymphangiogenesis can contribute to tumor metastasis. Lymphatic vessels are composed of lymphatic endothelial cells (LECs) that can be identified by distinct marker molecules such as Prox-1, podoplanin, VEGFR-3 and LYVE-1. Primary LECs represent a valuable tool for the study of basic functions of the lymphatic system. However, their isolation remains a challenge, particularly if rodent tissues are used as a source. We developed a method for the isolation of rat dermal LECs from the skin of newborn rats based on sequential enzymatic digestion with trypsin and Liberase followed by flow cytometric sorting using LYVE-1 specific antibodies. Cells isolated according to this protocol expressed the lymphatic markers Prox-1, podoplanin, LYVE-1 and VEGFR-3, and displayed an endothelial-like morphology when taken into culture. These primary cells can be used for studying lymphatic biology in rat models, and the protocol we describe here therefore represents an important extension of the experimental repertoire available for rats and for modeling the human lymphatic system.
Lymphangiogenesis
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Podoplanin
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Lymphatic Endothelium
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Lymphangiogenesis
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Objective To observe the morphology of lymphatics in the rat primary colonic cancer to provide the morphologic data for the study of the molecular mechanism of tumor metastasis. Method Wistar rats were used to establish the animal model of primary rat colonic cancer with MNNG to obtain the specimens in different stages. The lymphatics around the colonic cancer were observed with the methods of semithin section and electron-microscope. Results There were no lymphatics in the central region of carcinomas, but the density of the lymphatics was increased and the cavity of the lymphatics was dilated in the periphery region of cancer tissue. Under the electron-microscope, it was seen that the opening junction of lymphatic endothelial cells was widen and the damage of the lymphatic wall was found, the ultrastructure of lymphatic endothelium were changed in peripheral region of the cancer tissue. Conclusion The changes of the lymphatic endothelium in the periphery region of the colonic cancer tissue suggest that the cancer cells may enter lymphatic lumen through the opening of endothelial junction and the endothelial dissolution,the changes of the organelles of endothelial cell maybe related to the damage for lymphatic wall.
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Lymphatic Endothelium
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The lymphatic microvasculature is uniquely adapted for the continuous removal of interstitial fluid and proteins and is an important entry point for leukocytes and tumor cells. Specialized functions of lymphatics suggest differences in the molecular composition of the lymphatic and blood vascular endothelium. However, the extent to which the two cell types differ is still unclear, and few molecules that are truly specific to lymphatic endothelial cells have been identified to date. We have isolated primary lymphatic and blood microvascular endothelial cells from human skin by immunoselection with the lymphatic marker LYVE-1 and demonstrate that the two cell lineages express distinct sets of vascular markers and respond differently to growth factors and extracellular matrix. Comparative microarray analysis of gene-expression profiles revealed a number of unique molecular properties that distinguish lymphatic and blood vascular endothelium. The molecular profile of lymphatic endothelium seems to reflect characteristic functional and structural features of the lymphatic capillaries. Classification of the differentially expressed genes into functional groups revealed particularly high levels of genes implicated in protein sorting and trafficking, indicating a more active role of lymphatic endothelium in uptake and transport of molecules than previously anticipated. The identification of a large number of genes selectively expressed by lymphatic endothelium should facilitate the discovery of hitherto unknown lymphatic vessel markers and provide a basis for the analysis of the molecular mechanisms accounting for the characteristic functions of lymphatic capillaries.
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Lymphatic vessels play a role in maintaining fluid homeostasis by draining interstitial fluid. A failure in lymphatic drainage triggers interstitial fluid accumulation causing lymphedema, a major lymphatic disease. Since lymphatic drainage is influenced by lymphatic barrier function, bioengineered models that can assess lymphatic barrier function would be instrumental. We built a lymphatic vessel (LV) on-chip by fabricating a microfluidic device that includes a hollow microchannel embedded in hydrogel. Employing luminal flow in the microchannel, lymphatic endothelial cells (LECs) seeded in the microchannel formed an engineered LV exhibiting conduit structure. In the device, LECs formed permeable junctions in collagen hydrogel. However, adding fibronectin to the collagen tightened LEC junctions. We tested lymphatic barrier function by introducing dextran into lymphatic lumens. LECs in collagen showed permeable barriers. LECs in fibronectin/collagen showed enhanced barrier, which was reversed by integrin a5 inhibition. We knocked out lymphatic endothelial markers (LYVE-1 and podoplanin) and tested their roles in barrier function. We learned podoplanin deficiency tightened LEC junctions, whereas LYVE-1 did not show any effect on LEC junctions. Mechanistically, LECs expressed integrin alpha 5 that is inactivated in collagen. However, integrin alpha 5 can be activated either in fibronectin or in podoplanin deficiency, enhancing lymphatic barrier function. In conclusion, our LV-on-chip provides a platform for studying lymphatic barrier function, and reveals integrin alpha 5 as a regulator of lymphatic barrier function.
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Podoplanin
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Lymphangiogenesis
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Interstitial fluid
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Lymphatic malformations (LMs) are disfiguring congenital anomalies characterized by aberrant growth of lymphatic vessels. They are broadly categorized histopathologically as macrocystic and microcystic. Although sclerotherapy has shown some success in the treatment of macrocystic malformations, there has been less progress with developing treatment strategies for microcystic malformations. In this study, we characterized lymphatic endothelial cells isolated from lymphatic and lymphaticovenous malformations. When compared to cells from normal lymphatic vessels, we found that the primary cultured malformed cells are morphologically different and also exhibited differences in binding, proliferation, migration and tube formation. Transcriptome analysis identified several genes whose expression was substantially higher in malformed compared to normal lymphatic endothelium, including DIRAS3 and FOXF1. Further analysis of LM tissue samples revealed distinguishing gene expression patterns that could pave the way to understanding the molecular pathogenesis of LMs. Based on gene expression signatures, we propose a new hypothesis that the subtype of localized LMs could be formed because of disruptions in lymph node development.
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