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 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 Ligand-directed targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis

2015 ◽  
Vol 112 (8) ◽  
pp. 2521-2526 ◽  
Author(s):  
Dawn R. Christianson ◽  
Andrey S. Dobroff ◽  
Bettina Proneth ◽  
Amado J. Zurita ◽  
Ahmad Salameh ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessels ◽  
Melanoma Cells ◽  
Cell Interactions ◽  
Melanoma Metastasis ◽  
Lymphatic Endothelium ◽  
Lymphatic Endothelial Cells ◽  
Cell Surfaces ◽  
Surface Binding ◽  
Lymphatic Vasculature

Metastasis is the most lethal step of cancer progression in patients with invasive melanoma. In most human cancers, including melanoma, tumor dissemination through the lymphatic vasculature provides a major route for tumor metastasis. Unfortunately, molecular mechanisms that facilitate interactions between melanoma cells and lymphatic vessels are unknown. Here, we developed an unbiased approach based on molecular mimicry to identify specific receptors that mediate lymphatic endothelial–melanoma cell interactions and metastasis. By screening combinatorial peptide libraries directly on afferent lymphatic vessels resected from melanoma patients during sentinel lymphatic mapping and lymph node biopsies, we identified a significant cohort of melanoma and lymphatic surface binding peptide sequences. The screening approach was designed so that lymphatic endothelium binding peptides mimic cell surface proteins on tumor cells. Therefore, relevant metastasis and lymphatic markers were biochemically identified, and a comprehensive molecular profile of the lymphatic endothelium during melanoma metastasis was generated. Our results identified expression of the phosphatase 2 regulatory subunit A, α-isoform (PPP2R1A) on the cell surfaces of both melanoma cells and lymphatic endothelial cells. Validation experiments showed that PPP2R1A is expressed on the cell surfaces of both melanoma and lymphatic endothelial cells in vitro as well as independent melanoma patient samples. More importantly, PPP2R1A-PPP2R1A homodimers occur at the cellular level to mediate cell–cell interactions at the lymphatic–tumor interface. Our results revealed that PPP2R1A is a new biomarker for melanoma metastasis and show, for the first time to our knowledge, an active interaction between the lymphatic vasculature and melanoma cells during tumor progression.

scholarly journals Crosstalk between cancer cells and blood endothelial and lymphatic endothelial cells in tumour and organ microenvironment

2015 ◽  
Vol 17 ◽  
Author(s):  
Esak Lee ◽  
Niranjan B. Pandey ◽  
Aleksander S. Popel
Keyword(s):  
Endothelial Cells ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Tumour Growth ◽  
Tumour Progression ◽  
Lymphatic Vessels ◽  
Cell Types ◽  
Malignant Cell ◽  
Lymphatic Endothelial Cells ◽  
Tumour Blood

Tumour and organ microenvironments are crucial for cancer progression and metastasis. Crosstalk between multiple non-malignant cell types in the microenvironments and cancer cells promotes tumour growth and metastasis. Blood and lymphatic endothelial cells (BEC and LEC) are two of the components in the microenvironments. Tumour blood vessels (BV), comprising BEC, serve as conduits for blood supply into the tumour, and are important for tumour growth as well as haematogenous tumour dissemination. Lymphatic vessels (LV), comprising LEC, which are relatively leaky compared with BV, are essential for lymphogenous tumour dissemination. In addition to describing the conventional roles of the BV and LV, we also discuss newly emerging roles of these endothelial cells: their crosstalk with cancer cells via molecules secreted by the BEC and LEC (also called angiocrine and lymphangiocrine factors). This review suggests that BEC and LEC in various microenvironments can be orchestrators of tumour progression and proposes new mechanism-based strategies to discover new therapies to supplement conventional anti-angiogenic and anti-lymphangiogenic therapies.

scholarly journals Endothelin-1 Stimulates Lymphatic Endothelial Cells and Lymphatic Vessels to Grow and Invade

2009 ◽  
Vol 69 (6) ◽  
pp. 2669-2676 ◽  
Author(s):  
Francesca Spinella ◽  
Emirena Garrafa ◽  
Valeriana Di Castro ◽  
Laura Rosanò ◽  
Maria Rita Nicotra ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cells ◽  
Endothelin 1

Vascular Growth Factors and Lymphangiogenesis

2002 ◽  
Vol 82 (3) ◽  
pp. 673-700 ◽  
Author(s):  
Lotta Jussila ◽  
Kari Alitalo
Keyword(s):  
Endothelial Cells ◽  
Growth Factors ◽  
Lymphatic System ◽  
Lymphatic Vessels ◽  
The Body ◽  
Vascular Tumors ◽  
Vascular Endothelial ◽  
Lymphatic Endothelial Cells ◽  
Independent Manner ◽  
Tumor Spread

Blood and lymphatic vessels develop in a parallel, but independent manner, and together form the circulatory system allowing the passage of fluid and delivering molecules within the body. Although the lymphatic vessels were discovered already 300 years ago, at the same time as the blood circulation was described, the lymphatic system has remained relatively neglected until recently. This is in part due to the difficulties in recognizing these vessels in tissues because of a lack of specific markers. Over the past few years, several molecules expressed specifically in the lymphatic endothelial cells have been characterized, and knowledge about the lymphatic system has started to accumulate again. The vascular endothelial growth factor (VEGF) family of growth factors and receptors is involved in the development and growth of the vascular endothelial system. Two of its family members, VEGF-C and VEGF-D, regulate the lymphatic endothelial cells via their receptor VEGFR-3. With the aid of these molecules, lymphatic endothelial cells can be isolated and cultured, allowing detailed studies of the molecular properties of these cells. Also the role of the lymphatic endothelium in immune responses and certain pathological conditions can be studied in more detail, as the blood and lymphatic vessels seem to be involved in many diseases in a coordinated manner. Discoveries made so far will be helpful in the diagnosis of certain vascular tumors, in the design of specific treatments for lymphedema, and in the prevention of metastatic tumor spread via the lymphatic system.

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.

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 Proper migration of lymphatic endothelial cells requires survival and guidance cues from arterial mural cells

2021 ◽  
Author(s):  
Di Peng ◽  
Koji Ando ◽  
Marleen Gloger ◽  
Renae Skoczylas ◽  
Naoki Mochizuki ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Lymphatic Vessels ◽  
Vascular Network ◽  
Lymphatic Endothelial Cells ◽  
Future Design ◽  
Mural Cells ◽  
Cell Ablation ◽  
Growth Factor Signalling ◽  
Factor C

The migration of lymphatic endothelial cells (LECs) is key for the development of the complex and vast lymphatic vascular network that pervades most of the tissues in an organism. In zebrafish, arterial intersegmental vessels together with chemokines have been shown to promote lymphatic cell migration from the horizontal myoseptum (HM). Here we found that LECs departure from HM coincides with the emergence of mural cells around the intersegmental arteries, raising the possibility that arterial mural cells promote LEC migration. Our live imaging and cell ablation experiments revealed that LECs migrate slower and fail to establish the lymphatic vascular network in the absence of arterial mural cells. We determined that mural cells are a source for the C-X-C motif chemokine 12 (Cxcl12a and Cxcl12b) and vascular endothelial growth factor C (Vegfc). We showed that ERK, a downstream component of Vegfc-Vegfr3 singling cascade, is activated in migrating LECs and that both chemokine and growth factor signalling is required for the robust migration. Furthermore, Vegfc-Vegfr3 has a pro-survival role in LECs during the migration. Together, the identification of mural cells a source for signals that guide LEC migration and survival will be important in the future design for rebuilding lymphatic vessels in the disease contexts.

scholarly journals Structural and functional conservation of non-lumenized lymphatic endothelial cells in the mammalian leptomeninges

2019 ◽  
Vol 139 (2) ◽  
pp. 383-401 ◽  
Author(s):  
Shannon Shibata-Germanos ◽  
James R. Goodman ◽  
Alan Grieg ◽  
Chintan A. Trivedi ◽  
Bridget C. Benson ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Dura Mater ◽  
Lymphatic Vessels ◽  
Amyloid Β ◽  
Lymphatic Endothelial Cells ◽  
Cell Type ◽  
Functional Conservation ◽  
Spherical Inclusions ◽  
Lymphatic Markers ◽  
The Brain

Abstract The vertebrate CNS is surrounded by the meninges, a protective barrier comprised of the outer dura mater and the inner leptomeninges, which includes the arachnoid and pial layers. While the dura mater contains lymphatic vessels, no conventional lymphatics have been found within the brain or leptomeninges. However, non-lumenized cells called Brain/Mural Lymphatic Endothelial Cells or Fluorescent Granule Perithelial cells (muLECs/BLECs/FGPs) that share a developmental program and gene expression with peripheral lymphatic vessels have been described in the meninges of zebrafish. Here we identify a structurally and functionally similar cell type in the mammalian leptomeninges that we name Leptomeningeal Lymphatic Endothelial Cells (LLEC). As in zebrafish, LLECs express multiple lymphatic markers, containing very large, spherical inclusions, and develop independently from the meningeal macrophage lineage. Mouse LLECs also internalize macromolecules from the cerebrospinal fluid, including Amyloid-β, the toxic driver of Alzheimer’s disease progression. Finally, we identify morphologically similar cells co-expressing LLEC markers in human post-mortem leptomeninges. Given that LLECs share molecular, morphological, and functional characteristics with both lymphatics and macrophages, we propose they represent a novel, evolutionary conserved cell type with potential roles in homeostasis and immune organization of the meninges.

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
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