scholarly journals Cell Fate Determination of Lymphatic Endothelial Cells

2020 ◽  
Vol 21 (13) ◽  
pp. 4790
Author(s):  
Young Jae Lee
Keyword(s):  
Endothelial Cells ◽  
Immune Responses ◽  
Cell Fate ◽  
Dietary Fat ◽  
Vascular System ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Vasculature ◽  
Fat Uptake ◽  
Mammalian System

The lymphatic vasculature, along with the blood vasculature, is a vascular system in our body that plays important functions in fluid homeostasis, dietary fat uptake, and immune responses. Defects in the lymphatic system are associated with various diseases such as lymphedema, atherosclerosis, fibrosis, obesity, and inflammation. The first step in lymphangiogenesis is determining the cell fate of lymphatic endothelial cells. Several genes involved in this commitment step have been identified using animal models, including genetically modified mice. This review provides an overview of these genes in the mammalian system and related human diseases.

scholarly journals Organ-specific lymphatic vasculature: From development to pathophysiology

2017 ◽  
Vol 215 (1) ◽  
pp. 35-49 ◽  
Author(s):  
Tatiana V. Petrova ◽  
Gou Young Koh
Keyword(s):  
Endothelial Cells ◽  
Dietary Fat ◽  
Lymphatic Vessels ◽  
Developmental Origins ◽  
Lymphatic Endothelial Cells ◽  
Tissue Microenvironment ◽  
Organ Specific ◽  
Intestinal Lymphatics ◽  
Lymphatic Vasculature ◽  
Fat Uptake

Recent discoveries of novel functions and diverse origins of lymphatic vessels have drastically changed our view of lymphatic vasculature. Traditionally regarded as passive conduits for fluid and immune cells, lymphatic vessels now emerge as active, tissue-specific players in major physiological and pathophysiological processes. Lymphatic vessels show remarkable plasticity and heterogeneity, reflecting their functional specialization to control the tissue microenvironment. Moreover, alternative developmental origins of lymphatic endothelial cells in some organs may contribute to the diversity of their functions in adult tissues. This review aims to summarize the most recent findings of organotypic differentiation of lymphatic endothelial cells in terms of their distinct (patho)physiological functions in skin, lymph nodes, small intestine, brain, and eye. We discuss recent advances in our understanding of the heterogeneity of lymphatic vessels with respect to the organ-specific functional and molecular specialization of lymphatic endothelium, such as the hybrid blood-lymphatic identity of Schlemm’s canal, functions of intestinal lymphatics in dietary fat uptake, and discovery of meningeal lymphatic vasculature and perivascular brain lymphatic endothelial cells.

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice

Development ◽  
1999 ◽  
Vol 126 (13) ◽  
pp. 3015-3025 ◽  
Author(s):  
G.H. Fong ◽  
L. Zhang ◽  
D.M. Bryce ◽  
J. Peng
Keyword(s):  
Endothelial Cells ◽  
Population Density ◽  
Cell Fate ◽  
Vascular System ◽  
Primitive Streak ◽  
Cellular Level ◽  
Wild Type ◽  
Primary Defect ◽  
Knock Out ◽  
Vascular Channels

We previously demonstrated the essential role of the flt-1 gene in regulating the development of the cardiovascular system. While the inactivation of the flt-1 gene leads to a very severe disorganization of the vascular system, the primary defect at the cellular level was unknown. Here we report a surprising finding that it is an increase in the number of endothelial progenitors that leads to the vascular disorganization in flt-1(−/−) mice. At the early primitive streak stage (prior to the formation of blood islands), hemangioblasts are formed much more abundantly in flt-1(−/−) embryos. This increase is primarily due to an alteration in cell fate determination among mesenchymal cells, rather than to increased proliferation, migration or reduced apoptosis of flt-1(−/−) hemangioblasts. We further show that the increased population density of hemangioblasts is responsible for the observed vascular disorganization, based on the following observations: (1) both flt-1(−/−) and flt-1(+/+) endothelial cells formed normal vascular channels in chimaeric embryos; (2) wild-type endothelial cells formed abnormal vascular channels when their population density was significantly increased; and (3) in the absence of wild-type endothelial cells, flt-1(−/−) endothelial cells alone could form normal vascular channels when sufficiently diluted in a developing embryo. These results define the primary defect in flt-1(−/−) embryos at the cellular level and demonstrate the importance of population density of progenitor cells in pattern formation.

scholarly journals Lymphatic endothelial progenitors bud from the cardinal vein and intersomitic vessels in mammalian embryos

Blood ◽  
2012 ◽  
Vol 120 (11) ◽  
pp. 2340-2348 ◽  
Author(s):  
Ying Yang ◽  
José Manuel García-Verdugo ◽  
Mario Soriano-Navarro ◽  
R. Sathish Srinivasan ◽  
Joshua P. Scallan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Fluid Balance ◽  
Tissue Fluid ◽  
Lymphatic Endothelial Cells ◽  
Cardinal Vein ◽  
Cellular Processes ◽  
Mammalian Embryos ◽  
Lymphatic Vasculature ◽  
Lymphatic Network

Abstract The lymphatic vasculature preserves tissue fluid balance by absorbing fluid and macromolecules and transporting them to the blood vessels for circulation. The stepwise process leading to the formation of the mammalian lymphatic vasculature starts by the expression of the gene Prox1 in a subpopulation of blood endothelial cells (BECs) on the cardinal vein (CV) at approximately E9.5. These Prox1-expressing lymphatic endothelial cells (LECs) will exit the CV to form lymph sacs, primitive structures from which the entire lymphatic network is derived. Until now, no conclusive information was available regarding the cellular processes by which these LEC progenitors exit the CV without compromising the vein's integrity. We determined that LECs leave the CV by an active budding mechanism. During this process, LEC progenitors are interconnected by VE-cadherin–expressing junctions. Surprisingly, we also found that Prox1-expressing LEC progenitors were present not only in the CV but also in the intersomitic vessels (ISVs). Furthermore, as LEC progenitors bud from the CV and ISVs into the surrounding mesenchyme, they begin expressing the lymphatic marker podoplanin, migrate away from the CV, and form the lymph sacs. Analyzing this process in Prox1-null embryos revealed that Prox1 activity is necessary for LEC progenitors to exit the CV.

Prox1 expression is negatively regulated by miR-181 in endothelial cells

Blood ◽  
2010 ◽  
Vol 116 (13) ◽  
pp. 2395-2401 ◽  
Author(s):  
Jan Kazenwadel ◽  
Michael Z. Michael ◽  
Natasha L. Harvey
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Vascular Endothelial Cells ◽  
Vascular Development ◽  
Lymphatic Endothelial Cell ◽  
Mrna Levels ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
Prox1 Expression

Abstract The specification of arterial, venous, and lymphatic endothelial cell fate is critical during vascular development. Although the homeobox transcription factor, Prox1, is crucial for the specification and maintenance of lymphatic endothelial cell identity, little is known regarding the mechanisms that regulate Prox1 expression. Here we demonstrate that miR-181a binds the 3′ untranslated region of Prox1, resulting in translational inhibition and transcript degradation. Increased miR-181a activity in primary embryonic lymphatic endothelial cells resulted in substantially reduced levels of Prox1 mRNA and protein and reprogramming of lymphatic endothelial cells toward a blood vascular phenotype. Conversely, treatment of primary embryonic blood vascular endothelial cells with miR-181a antagomir resulted in increased Prox1 mRNA levels. miR-181a expression is significantly higher in embryonic blood vascular endothelial cells compared with lymphatic endothelial cells, suggesting that miR-181 activity could be an important mechanism by which Prox1 expression is silenced in the blood vasculature during development. Our work is the first example of a microRNA that targets Prox1 and has implications for the control of Prox1 expression during vascular development and neo-lymphangiogenesis.

scholarly journals Single-cell mapping reveals new markers and functions of lymphatic endothelial cells in lymph nodes

2020 ◽  
Author(s):  
Noriki Fujimoto ◽  
Yuliang He ◽  
Marco D’Addio ◽  
Carlotta Tacconi ◽  
Michael Detmar ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Single Cell ◽  
Cancer Metastasis ◽  
Lymphatic Vessels ◽  
Peripheral Tolerance ◽  
Lymphatic Endothelial Cells ◽  
Subcapsular Sinus ◽  
Lymphocyte Egress

ABSTRACTLymph nodes (LNs) are highly organized secondary lymphoid organs that mediate adaptive immune responses to antigens delivered via afferent lymphatic vessels. Lymphatic endothelial cells (LECs) line intranodal lymphatic sinuses and organize lymph and antigen distribution. LECs also directly regulate T cells, mediating peripheral tolerance to self-antigens, and play a major role in many diseases including cancer metastasis. However, little is known about the phenotypic and functional heterogeneity of LN LECs. Using single-cell RNA sequencing, we comprehensively defined the transcriptome of LECs in murine skin-draining LNs, and identified new markers and functions of distinct LEC subpopulations. We found that LECs residing in the subcapsular sinus have an unanticipated function in scavenging of modified LDL and also identified a specific cortical LEC subtype implicated in rapid lymphocyte egress from LNs. Our data provide new insights into the diversity of LECs in murine lymph nodes and a rich resource for future studies into the regulation of immune responses by lymph node LECs.

scholarly journals Zebrafish prox1b Mutants Develop a Lymphatic Vasculature, and prox1b Does Not Specifically Mark Lymphatic Endothelial Cells

PLoS ONE ◽  
2011 ◽  
Vol 6 (12) ◽  
pp. e28934 ◽  
Author(s):  
Shijie Tao ◽  
Merlijn Witte ◽  
Robert J. Bryson-Richardson ◽  
Peter D. Currie ◽  
Benjamin M. Hogan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Vasculature

Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo

Development ◽  
2001 ◽  
Vol 128 (10) ◽  
pp. 1717-1730 ◽  
Author(s):  
M.A. Dyer ◽  
S.M. Farrington ◽  
D. Mohn ◽  
J.R. Munday ◽  
M.H. Baron
Keyword(s):  
Endothelial Cells ◽  
Cell Fate ◽  
Mouse Embryo ◽  
Hedgehog Signaling ◽  
Vascular System ◽  
Vascular Endothelial Cells ◽  
Indian Hedgehog ◽  
Vascular Endothelial ◽  
Primitive Endoderm ◽  
Genes Encoding

During gastrulation in the mouse, mesoderm is induced and patterned by secreted signaling molecules, giving rise first to primitive erythroblasts and vascular endothelial cells. We have demonstrated previously that development of these lineages requires a signal(s) secreted from the adjacent primitive endoderm. We now show that Indian hedgehog (Ihh) is a primitive endoderm-secreted signal that alone is sufficient to induce formation of hematopoietic and endothelial cells. Strikingly, as seen with primitive endoderm, Ihh can respecify prospective neural ectoderm (anterior epiblast) along hematopoietic and endothelial (posterior) lineages. Downstream targets of the hedgehog signaling pathway (the genes encoding patched, smoothened and Gli1) are upregulated in anterior epiblasts cultured in the presence of Ihh protein, as is Bmp4, which may mediate the effects of Ihh. Blocking Ihh function in primitive endoderm inhibits activation of hematopoiesis and vasculogenesis in the adjacent epiblast, suggesting that Ihh is an endogenous signal that plays a key role in the development of the earliest hemato-vascular system. To our knowledge, these are the earliest functions for a hedgehog protein in post-implantation development in the mouse embryo.

scholarly journals Lymphovenous hemostasis and the role of platelets in regulating lymphatic flow and lymphatic vessel maturation

Blood ◽  
2016 ◽  
Vol 128 (9) ◽  
pp. 1169-1173 ◽  
Author(s):  
John D. Welsh ◽  
Mark L. Kahn ◽  
Daniel T. Sweet
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Vascular System ◽  
Lymphatic Vessels ◽  
Lymph Flow ◽  
The Body ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Circulation ◽  
Vessel Maturation

Abstract Aside from the established role for platelets in regulating hemostasis and thrombosis, recent research has revealed a discrete role for platelets in the separation of the blood and lymphatic vascular systems. Platelets are activated by interaction with lymphatic endothelial cells at the lymphovenous junction, the site in the body where the lymphatic system drains into the blood vascular system, resulting in a platelet plug that, with the lymphovenous valve, prevents blood from entering the lymphatic circulation. This process, known as “lymphovenous hemostasis,” is mediated by activation of platelet CLEC-2 receptors by the transmembrane ligand podoplanin expressed by lymphatic endothelial cells. Lymphovenous hemostasis is required for normal lymph flow, and mice deficient in lymphovenous hemostasis exhibit lymphedema and sometimes chylothorax phenotypes indicative of lymphatic insufficiency. Unexpectedly, the loss of lymph flow in these mice causes defects in maturation of collecting lymphatic vessels and lymphatic valve formation, uncovering an important role for fluid flow in driving endothelial cell signaling during development of collecting lymphatics. This article summarizes the current understanding of lymphovenous hemostasis and its effect on lymphatic vessel maturation and synthesizes the outstanding questions in the field, with relationship to human disease.

scholarly journals Liprin β1 is highly expressed in lymphatic vasculature and is important for lymphatic vessel integrity

Blood ◽  
2010 ◽  
Vol 115 (4) ◽  
pp. 906-909 ◽  
Author(s):  
Camilla Norrmén ◽  
Wouter Vandevelde ◽  
Annelii Ny ◽  
Pipsa Saharinen ◽  
Massimiliano Gentile ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessel ◽  
Lipid Absorption ◽  
Tissue Fluid ◽  
Lymphatic Endothelial Cells ◽  
Isolation And Characterization ◽  
Lymphatic Vasculature ◽  
Vessel Integrity

Abstract The lymphatic vasculature is important for the regulation of tissue fluid homeostasis, immune response, and lipid absorption, and the development of in vitro models should allow for a better understanding of the mechanisms regulating lymphatic vascular growth, repair, and function. Here we report isolation and characterization of lymphatic endothelial cells from human intestine and show that intestinal lymphatic endothelial cells have a related but distinct gene expression profile from human dermal lymphatic endothelial cells. Furthermore, we identify liprin β1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, as highly expressed in intestinal lymphatic endothelial cells in vitro and lymphatic vasculature in vivo, and show that it plays an important role in the maintenance of lymphatic vessel integrity in Xenopus tadpoles.

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