scholarly journals Cells with Many Talents: Lymphatic Endothelial Cells in the Brain Meninges

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 799
Author(s):  
Irina Suárez ◽  
Stefan Schulte-Merker
Keyword(s):  
Endothelial Cells ◽  
Single Cells ◽  
Lymphatic Vessels ◽  
Gene Expression Signature ◽  
Brain Parenchyma ◽  
Dietary Fats ◽  
Lymphatic Endothelial Cells ◽  
Edema Formation ◽  
Peripheral Tissues ◽  
The Brain

The lymphatic system serves key functions in maintaining fluid homeostasis, the uptake of dietary fats in the small intestine, and the trafficking of immune cells. Almost all vascularized peripheral tissues and organs contain lymphatic vessels. The brain parenchyma, however, is considered immune privileged and devoid of lymphatic structures. This contrasts with the notion that the brain is metabolically extremely active, produces large amounts of waste and metabolites that need to be cleared, and is especially sensitive to edema formation. Recently, meningeal lymphatic vessels in mammals and zebrafish have been (re-)discovered, but how they contribute to fluid drainage is still not fully understood. Here, we discuss these meningeal vessel systems as well as a newly described cell population in the zebrafish and mouse meninges. These cells, termed brain lymphatic endothelial cells/Fluorescent Granular Perithelial cells/meningeal mural lymphatic endothelial cells in fish, and Leptomeningeal Lymphatic Endothelial Cells in mice, exhibit remarkable features. They have a typical lymphatic endothelial gene expression signature but do not form vessels and rather constitute a meshwork of single cells, covering the brain surface.

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 Dense poly(ethylene glycol) coatings maximize nanoparticle transport across lymphatic endothelial cells

2020 ◽  
Author(s):  
Jacob McCright ◽  
Colin Skeen ◽  
Jenny Yarmovsky ◽  
Katharina Maisel
Keyword(s):  
Endothelial Cells ◽  
Ethylene Glycol ◽  
Lymph Nodes ◽  
Lymphatic Vessels ◽  
Lymphatic Endothelial Cells ◽  
Poly Ethylene Glycol ◽  
Nanoparticle Transport ◽  
Peripheral Tissues ◽  
Transport Efficiency ◽  
Poly Ethylene

AbstractLymphatic vessels have received considerable attention in recent years as delivery route for immune modulatory therapies to the lymph nodes. Lymph node targeting of immunotherapies and vaccines has been shown to significantly enhance their therapeutic efficacy. Lymphatics transport functions materials from peripheral tissues to the lymph nodes, including small 10 – 250 nm therapeutic nanoparticles. While size required to enter lymphatic vessels, surface chemistry is more poorly studied. Here, we probed the effects of surface poly(ethylene glycol) (PEG) density on nanoparticle transport across lymphatic endothelial cells (LECs). We differentially PEGylated model carboxylate-modified polystyrene nanoparticles to form either a brush or dense brush PEG conformation on the nanoparticle surfaces. Using an established in-vitro lymphatic transport model, we found that the addition of any PEG improved the transport of nanoparticles through lymphatic endothelial cells (2.5 - 2.6 ± 0.9% transport efficiency at 24 hours) compared to the unmodified PS-COOH nanoparticles (0.05 ± 0.05% transport efficiency at 24 hours). Additionally, we found that transcellular transport is maximized (4.2 ± 0.7% transport efficiency at 24 hours) when the PEG is in a dense brush conformation on nanoparticle surfaces, corresponding with a high grafting density (Rf/D = 4.9). These results suggest that PEG conformation has a crucial role in determining translocation of nanoparticles across LECs and into lymphatic vessels. Thus, we identified PEG density as a major design criteria for maximizing lymphatic targeting of therapeutic nanoparticle formulations that can be widely applied to enhance immunotherapeutic and vaccine outcomes in future studies.

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 Cerebral Edema Formation After Stroke: Emphasis on Blood–Brain Barrier and the Lymphatic Drainage System of the Brain

2021 ◽  
Vol 15 ◽  
Author(s):  
Sichao Chen ◽  
Linqian Shao ◽  
Li Ma
Keyword(s):  
Blood Brain Barrier ◽  
Cerebral Edema ◽  
Lymphatic System ◽  
Vasogenic Edema ◽  
Lymphatic Vessels ◽  
Drainage System ◽  
Brain Barrier ◽  
Edema Formation ◽  
Blood Brain ◽  
The Brain

Brain edema is a severe stroke complication that is associated with prolonged hospitalization and poor outcomes. Swollen tissues in the brain compromise cerebral perfusion and may also result in transtentorial herniation. As a physical and biochemical barrier between the peripheral circulation and the central nervous system (CNS), the blood–brain barrier (BBB) plays a vital role in maintaining the stable microenvironment of the CNS. Under pathological conditions, such as ischemic stroke, the dysfunction of the BBB results in increased paracellular permeability, directly contributing to the extravasation of blood components into the brain and causing cerebral vasogenic edema. Recent studies have led to the discovery of the glymphatic system and meningeal lymphatic vessels, which provide a channel for cerebrospinal fluid (CSF) to enter the brain and drain to nearby lymph nodes and communicate with the peripheral immune system, modulating immune surveillance and brain responses. A deeper understanding of the function of the cerebral lymphatic system calls into question the known mechanisms of cerebral edema after stroke. In this review, we first discuss how BBB disruption after stroke can cause or contribute to cerebral edema from the perspective of molecular and cellular pathophysiology. Finally, we discuss how the cerebral lymphatic system participates in the formation of cerebral edema after stroke and summarize the pathophysiological process of cerebral edema formation after stroke from the two directions of the BBB and cerebral lymphatic system.

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

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 Epithelioid and spindle-cell haemangioendothelioma in the brain of a dog: a case report

2018 ◽  
Vol 63 (No. 4) ◽  
pp. 193-197 ◽  
Author(s):  
T. Yaman ◽  
A. Uyar ◽  
OF Keles ◽  
Z. Yener
Keyword(s):  
Endothelial Cells ◽  
Blood Cells ◽  
Spindle Cell ◽  
Clinical Symptoms ◽  
Brain Parenchyma ◽  
Tumour Cells ◽  
Macroscopic Findings ◽  
The Right ◽  
The Brain ◽  
Cut Surface

A 9.5-year-old male Belgian malinois dog died after showing clinical symptoms that included fatigue, anorexia and dyspnoea. Necropsy revealed macroscopic findings in the brain and other organs. A solitary, brown-red-coloured mass, approximately 0.5 cm thick and 1.5 × 2 cm in diameter, was detected on the right side of the medulla oblongata, pons and cerebellum. The cut surface showed no invasion of the brain parenchyma. Histologically, the neoplasm was characterised by proliferation of endothelial cells, which showed epithelioid and spindle cell features. Some tumour cells had intracytoplasmic lumen formations containing red blood cells. The nuclei of the tumour cells were large and vesicular. In immunohistochemical experiments the tumour cells stained positive for factor VIII-related antigen, CD31 and CD34. A description is provided of the features of this epithelioid and spindle-cell haemangioendothelioma (EHE) that originated from vessels of the meninges in the subarachnoid space.

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 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.

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