Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single-cell analysis reveals heterogeneity of high endothelial venules and different regulation of genes controlling lymphocyte entry to lymph nodes

ABSTRACT: High endothelial venules (HEVs) are specialized blood vessels allowing recirculation of naïve lymphocytes through lymphoid organs. Here, using full length single-cell RNA sequencing, RNA-FISH, flow cytometry and immunohistofluorescence, we reveal the heterogeneity of HEVs in adult mouse peripheral lymph nodes (PLNs) under conditions of homeostasis, antigenic stimulation and after inhibition of lymphotoxin-b receptor (LTbR) signaling. We demonstrate that HEV endothelial cells are in an activated state during homeostasis, and we identify the genes characteristic of the differentiated HEV phenotype. We show that LTbR signaling regulates many HEV genes and pathways in resting PLNs, and that immune stimulation induces a global and temporary inflammatory phenotype in HEVs without compromising their ability to recruit naïve lymphocytes. Most importantly, we uncover differences in the regulation of genes controlling lymphocyte trafficking, Glycam1, Fut7, Gcnt1, Chst4, B3gnt3 and Ccl21a, that have implications for HEV function and regulation in health and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE106514 | GEO | 2019/03/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcriptome Analysis of Tumor Associated High Endothelial Venules in Breast Cancer

Project description:High endothelial venules (HEVs) are specialized post-capillary venules that recruit naïve lymphocytes to the lymph nodes and are essential for the development of adaptive immunity. HEVs can also develop in tumors. These specialized tumor vessels are thought to be important for recruiting naïve T cells and B cells into tumors and locally enhancing anti-tumor immunity by supporting the formation of tertiary lymphoid structures. By a comparative transcriptome analysis in human breast cancer, we investigated differentially expressed genes between tumor-associated HEVs and the rest of the tumor vasculature. Tumor vessels highly expressing HEV-upregulated genes, such as the homeobox gene MEOX2 and the tetraspanin gene TSPAN7, were associated with extensive infiltration of T and B lymphocytes and the occurrence of tertiary lymphoid structures, which is known to predict therapeutic responses to immune checkpoint inhibitors. Moreover, high transcript counts of these genes in clinical tumor specimens were associated with a significant survival benefit in advanced breast cancer. The molecular signature of HEVs identified here may be useful for guiding immunotherapies and provide a new direction for investigating tumor-associated HEVs and their clinical significance.

2022-03-31 | GSE196703 | GEO

Single cell RNA-sequencing of Tumor-Associated High Endothelial Cells (TA-HECs) and comparison to their counterparts in homeostatic and inflamed mouse lymph nodes

Project description:High endothelial venules (HEVs) are specialized postcapillary venules that mediate lymphocyte trafficking from the blood into lymph nodes. HEV-like blood vessels are found in solid tumors in association with CD8+ T cell infiltration.This study uses single cell RNA-sequencing using the Fluidigm C1 system as a method to evaluate the transcriptome in lymph node and tumor-associated HEV endothelial cells (LN-HECs and TA-HECs). We isolated MECA-79+ TA-HECs and CD31+MECA-79- tumor-associated endothelial cells (TA-ECs) by cell sorting and we compared their transcriptome to those of their counterparts in homeostatic (LN-HECs and LN-ECs) or inflamed (iLN-HECs) lymph nodes. TA-HECs express high levels of endothelial cell markers Cdh5 and Pecam1 (CD31), post-capillary venule marker Ackr1 (DARC) and venous transcription factor Nr2f2, indicating that they correspond to post-capillary venule endothelium, like their lymph node counterparts. The genes encoding HEV sialomucins decorated by the sulfated MECA-79 epitope (CD34 and Emcn, endomucin) and the core 1 branching enzyme B3gnt3 that is essential for its biosynthesis, are equally expressed in all HEC populations, whereas sulfotransferases Chst2 and Chst4 are expressed at lower levels in TA-HECs. Although TA-HECs are molecularly distinct from lymph node HECs, they share several important characteristics with iLN-HECs, including the upregulation of endothelial selectins (Selp, Sele) and inflammatory chemokines CXCL9 and CXCL10, the ligands for chemokine receptor CXCR3 on effector T cells. Finally, endothelial cell adhesion molecules ICAM1, ICAM2 and VCAM1 that are important for lymphocyte sticking to HEVs, are expressed at similar levels in all HECs. Together, these findings indicated that MECA-79+ TA-HECs, similar to HECs in immune-stimulated lymph nodes, exhibit an inflamed phenotype characterized by co-expression of MECA-79+ antigens with endothelial selectins and inflammatory chemokines.

2021-12-14 | GSE154898 | GEO

LTBR-mediated immunomodulation of the tumor microenvironment promotes anti-tumor responses

Project description:The presence of high endothelial venules (HEV) and tertiary lymphoid structures (TLS) in solid tumors is correlated with favorable prognosis in many cancer types and has been associated with better treatment responses to immune-checkpoint blockade (ICB). However, the molecular mechanisms underlying intratumoral HEV and TLS formation and their contribution to anti-tumor responses remain unclear. Lymphotoxin beta receptor (LTBR) signaling is a critical regulator of lymph node organogenesis and when combined with antiangiogenic and ICB treatment can augment tumor-associated HEV formation. Here we demonstrate that LTBR signaling modulates the tumor microenvironment via multiple mechanisms to promote anti-tumor T cell responses. Systemic activation of the LTBR pathway via agonistic antibody treatment induced tumor-specific HEV formation, upregulated the expression of TLS-related chemokines, and enhanced dendritic cell (DC) and T cell infiltration and activation in syngeneic tumor models. In vitro studies confirmed direct effects of LTBR agonism on DC activation and maturation and associated DC- mediated T cell activation. Single agent LTBR agonist treatment inhibited syngeneic tumor growth in a CD8+ T cell- and HEV-dependent manner; and the LTBR agonist enhanced anti-tumor effects of anti-PD-1 and CAR T cell therapies, respectively. An in vivo tumor screen for TLS-inducing cytokines revealed that the combination of LTBR agonism and lymphotoxin alpha (LT⍺) expression promoted robust intratumoral TLS induction and enhanced tumor responses to anti-CTLA-4 treatment. Collectively, this study highlights crucial functions of LTBR signaling in modulating the tumor microenvironment and inform future HEV/TLS- based strategies for cancer treatments.

2024-08-08 | GSE243170 | GEO

Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop [SmartSeq2]

Project description:The lack of T cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLLSs), which are the local site of humoral and cellular immune responses against cancers, is associated with good prognosis, and they have recently been detected in immune checkpoint blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing single-cell transcriptomics, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke transdifferentiation of postcapillary venules into inflamed high-endothelial venules (HEVs) via lymphotoxin/lymphotoxin beta receptor (LT/LTβR) signaling. In turn, tumor HEVs boost intratumoral lymphocyte influx and foster permissive lymphocyte niches for PD1- and PD1+TCF1+ CD8 T cell progenitors that differentiate into GrzB+PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived signals revealing that tumor HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop.

2022-11-02 | GSE198069 | GEO

Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop [10X Genomics]

2022-11-02 | GSE198079 | GEO

Overexpression of brain endothelial mucin-type O-glycan biosynthesis promotes brain homeostasis in aged mice

Project description:In our study, we find that AAV-mediated brain endothelial B3GNT3 overexpression reduces neuroinflammatory markers and cognitive deficits in aged mice. Here, we perform snRNA-seq to characterize the cellular and molecular changes induced by brain endothelial B3GNT3 overexpression.

2024-12-17 | GSE268642 | GEO

The gene expression of HUVEC in response to the cytokine stimulations

Project description:The response of endothelial cells to the tissue environment has a critical impact on their function in inflammation and tumors. In particular, cytokine stimulation such as TNFa, IL-4, IFNg, and LTbR induces gene expression changes, which significantly impact endothelial cell function and differentiation. To understand the degree of gene expression change, we performed a transcriptome analysis of HUVEC.

2024-05-01 | GSE254958 | GEO

Exon level expression profile of submandibular glands in female MyD88+/+ and MyD88−/− NOD mice.

Project description:Transcriptome analysis of submandibular glands in female MyD88+/+ and MyD88−/− NOD mice. Sjögren's syndrome (SS) is an autoimmune disease characterized by dysfunction of salivary glands (SGs) and lacrimal glands, which is caused by chronic inflammation associated with autoantibody and autoreactive lymphocyte infiltration. The pathogenic mechanism of SS has not been fully elucidated. Infiltrated lymphocytes form regularized structures similar to lymphoid follicles of secondary lymphoid organs, such as T/B cell compartments, high endothelial venules (HEVs), lymphatic vessels, and germinal centers, therefore being believed as an ectopic lymphoid tissue called tertiary lymphoid organs (TLO). We previously found that deletion of the Toll-like receptor/IL-1 receptor (TLR/IL-1R) adaptor molecule gene Myd88 in SS model mice NOD reduced the frequency of lymphocyte infiltration and HEV formation in SGs. In this study, we analyzed the effect of MyD88 deficiency on lymphoid follicle formation in SGs of NOD mice. Microarray analysis showed decreased expression of genes related to TLO, such as Cxcl13 and Cxcr5, in Myd88-deficient SGs. These results indicate that deficiency of TLR/IL-1R signaling decrease gene expression ot chemokines in SGs, suggesting MyD88-dependent signaling is directly involved in formation of lymphoid follicles in SS.

2021-09-01 | GSE157669 | GEO

Lymphoma-induced regression of high endothelial venules impairs homeostatic lymphocyte trafficking

Project description:Lymphoma growth is facilitated by the well-balanced infrastructure of the microenvironment in lymph nodes (LN). LNs undergo rapid expansion during lymphoma progression, often accompanied by excessive blood vessel growth. Here we report that aggressive lymphoma cause severe high endothelial venule (HEV) regression which impairs lymphocyte recirculation. In this study, we used transferred (i.v.) Eµ-Myc tumor cells as a mouse model of aggressive lymphoma. Blood endothelial cells from tumor bearing and control LNs were isolated by FACS and processed for single-cell RNA sequencing. The results revealed a detrimental mechanisms causing HEV-dedifferentiation during lymphoma growth with potential implications on tumor-targeting immune surveillance and strategies of immune therapy in LNs

2021-10-14 | E-MTAB-10389 | biostudies-arrayexpress

Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing

Project description:This file contains gene microarray data from FACS purified mouse high endothelial cells and capillary endothelial cells from peripheral lymph nodes, mesenteric lymph nodes, and Peyer’s patches. The data will allow for better understanding of the specialization of high endothelial venules (HEV) and their role in lymphocyte recruitment from the blood; the tissue-specific differentiation of lymphoid tissue vasculature; and the specialized features of capillary vs. post-capillary endothelium, including differences in signaling pathways, adhesive properties and mechanisms of hemostasis. We analyzed transcript expression data from vascular endothelial subsets from BALB/c mouse lymphoid tissue.

2014-08-31 | E-GEOD-58056 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data