Browse
Submit Data
Databases
API
Help

Dataset Information

30 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Gene Signatures Detect Damaged Liver Sinusoidal Endothelial Cells in Chronic Liver Diseases

ABSTRACT: Liver sinusoidal endothelial cells have a gatekeeper function in liver homeostasis by permitting substrates from the bloodstream into the space of Disse and regulating hepatic stellate cell activation status. Maintenance of LSEC's highly specialized phenotype is crucial for liver homeostasis. During liver fibrosis and cirrhosis, LSEC phenotype and functions are lost by processes known as capillarization and LSEC dysfunction. LSEC capillarization can be demonstrated by the loss of fenestrae (cytoplasmic pores) and the manifestation of a basement membrane. Currently, no protein or genetic markers can clearly distinguish healthy from damaged LSECs in acute or chronic liver disease. Single cell (sc)RNA sequencing efforts have identified several LSEC populations in mouse models for liver disease and in human cirrhotic livers. Still, there are no clearly defined genesets that can identify LSECs or dysfunctional LSEC populations in transcriptome data. Here, we developed genesets that are enriched in healthy and damaged LSECs which correlated very strongly with healthy and early stage- vs. advanced human liver diseases. A damaged LSEC signature comprised of Fabp4/5 and Vwf/a1 was established which could efficiently identify damaged endothelial cells in single cell RNAseq data sets. In LSECs from an acute CCl4 liver injury mouse model, Fabp4/5 and Vwf/a1 expression is induced within 1–3 days while in cirrhotic human livers these 4 genes are highly enriched in damaged LSECs. In conclusion, our newly developed gene signature of damaged LSECs can be applicable to a wide range of liver disease etiologies, implicating a common transcriptional alteration mechanism in LSEC damage.

SUBMITTER: Verhulst S

PROVIDER: S-EPMC8564042 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Gene signatures detect damaged LSECs in all chronic liver diseases.

Project description:Transcriptional alterations in LSECs from healthy and damaged livers were determined using RNA Sequencing. Models include acute liver injury (1 ip injection of CCl4) with different timepoints during recovery. Illumina NextSeq 500 High was used for sequencing.

2021-10-08 | GSE180366 | GEO

Gene signatures detect damaged LSECs in all chronic liver diseases.

Project description:Gene signatures detect damaged LSECs in all chronic liver diseases.

| PRJNA748010 | ENA

Liver sinusoidal endothelial cells (LSECs) modifications in patients with chronic hepatitis C.

Project description:The sinusoidal endothelial cells present in the liver (LSECs) are tipically characterized by the presence of pores (fenestrae). During some pathological conditions LSECs undergo "capillarization", a process characterized by loss of fenestrations and acquisition of a vascular phenotype. In chronic liver disease capillarization has been reported to precede the development of fibrosis. LSECs modification in the setting of HCV infection is currently poorly investigated. Considering that HCV accounts for important changes in hepatocytes and in view of the intimate connection between hepatocytes and LSECs, here we set out to study in great detail the LSECs modifications in individuals with HCV-dependent chronic hepatitis. Electron microscopy analysis, and evaluation of CD32, CD31 and caveolin-1 expression showed that in HCV infection LSECs display major morphological changes but maintain their phenotypical identity. Capillarization was observed only in cases at initial stages of fibrosis. Our findings showed that the severity of LSECs modifications appears to be correlated with hepatocytes damage and fibrosis stage providing novel insight in the pathogenesis of HCV-chronic hepatitis.

| S-EPMC6584733 | biostudies-literature

Capillarized Liver Sinusoidal Endothelial Cells Undergo Partial Endothelial-Mesenchymal Transition to Actively Deposit Sinusoidal ECM in Liver Fibrosis.

Project description:Tissue-specific endothelial cells are more than simply a barrier lining capillaries and are proved to be capable of remarkable plasticity to become active collagen matrix-producing myofibroblasts (MFs) in solid organs with fibrosis. Liver sinusoidal endothelial cells (LSECs) also participate in the development of hepatic fibrosis, but the exact roles and underlying mechanism have been poorly understood in addition to capillarization. In this study, we demonstrate, by using single-cell RNA sequencing, lineage tracing, and colocalization analysis, that fibrotic LSECs undergo partial endothelial mesenchymal transition (EndMT) with a subset of LSECs acquiring an MF-like phenotype. These phenotypic changes make LSECs substantial producers of extracellular matrix (ECM) preferentially deposited in liver sinusoids but not septal/portal scars as demonstrated by immunofluorescence in animal models and patients with fibrosis/cirrhosis, likely due to their limited migration. Bioinformatic analysis verifies that LSECs undergo successive phenotypic transitions from capillarization to mesenchymal-like cells in liver fibrosis. Furthermore, blockade of LSEC capillarization by using YC-1, a selective eNOS-sGC activator, effectively attenuates liver damage and fibrogenesis as well as mesenchymal features of LSECs, suggesting that capillarization of LSECs might be upstream to their mesenchymal transition during fibrosis. In conclusion, we report that capillarized LSECs undergo a partial EndMT characterized by increased ECM production without activating cell mobility, leading to perisinusoidal ECM deposition that aggravate liver function and fibrogenesis. Targeting this transitional process may be of great value for antifibrotic treatment of liver fibrosis.

| S-EPMC8285099 | biostudies-literature

Liver sinusoidal endothelial cells - gatekeepers of hepatic immunity.

Project description:Liver sinusoidal endothelial cells (LSECs) line the low shear, sinusoidal capillary channels of the liver and are the most abundant non-parenchymal hepatic cell population. LSECs do not simply form a barrier within the hepatic sinusoids but have vital physiological and immunological functions, including filtration, endocytosis, antigen presentation and leukocyte recruitment. Reflecting these multifunctional properties, LSECs display unique structural and phenotypic features that differentiate them from the capillary endothelium present within other organs. It is now clear that LSECs have a critical role in maintaining immune homeostasis within the liver and in mediating the immune response during acute and chronic liver injury. In this Review, we outline how LSECs influence the immune microenvironment within the liver and discuss their contribution to immune-mediated liver diseases and the complications of fibrosis and carcinogenesis.

| S-EPMC7096836 | biostudies-literature

PROTEOMIC ANALYSIS OF DYSFUNCTIONAL LIVER SINUSOIDAL ENDOTHELIAL CELLS REVEALS SUBSTANTIAL DIFFERENCES IN MOST COMMON EXPERIMENTAL MODELS OF CHRONIC LIVER DISEASES.

Project description:Molecular markers of dedifferentiation of dysfunctional liver sinusoidal endothelial cells (LSEC), have not been fully elucidated. We aimed at deciphering the molecular profile of dysfunctional LSEC in different pathological scenarios. Flow cytometry was used to sort CD11bˉ/CD32b+ and CD11bˉ/CD32bˉLSEC from three rat models of liver disease (bile duct ligation-BDL, inhaled carbon tetrachloride-CCl4 and high fat glucose/fructose diet-HFGFD). Full proteomic profile was performed applying nano-scale liquid chromatography tandem mass spectrometry (nLC-MS) and analyzed with PEAKS software. The percentage of CD32bˉ LSEC varied across groups, suggesting different capillarization processes. Both CD32+ and CD32bˉLSEC from models are different from control LSEC but differently expressed proteins in CD32bˉLSEC are significantly higher. Heatmaps evidenced specific protein expression patterns for each model. Analysis of biological significance comparing dysfunctional CD32bˉLSEC with specialized CD32b+ LSEC from controls showed central similarities represented by 45 common downregulated proteins involved in the suppression of the endocytic machinery and 63 common upregulated proteins associated with the actin-dependent cytoskeleton reorganization. In summary, substantial differences but also similarities in dysfunctional LSEC from the three most common models of liver disease were found, supporting the idea that LSEC may harbor different protein expression profiles according to the etiology or disease stage.

2023-10-24 | PXD040661 | Pride

Signature of gene expression profile of liver sinusoidal endothelial cells in nonalcoholic steatohepatitis.

Project description:Background: There has been emerging evidence that liver sinusoidal endothelial cells (LSECs) play an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH). This study aims to figure out the signature of the gene expression profile of LSECs in NASH and to explore potential biomarkers related to damaged LSECs in NASH. Methods and materials: Animal experiments were performed to demonstrate the significant structural damage of LSECs in the NASH model. To further understand the functional changes of these damaged LSECs in NASH, we used the public GEO database that contained microarray data for the gene expression of LSECs in NASH and normal mouse liver. Differentially expressed genes (DEGs) were analyzed, and further Gene Ontology (GO) enrichment analysis was performed to understand the functional changes. The hub genes were then identified and validated via external GEO databases. Results: There was significant structural damage to LSECs in the NASH model, accompanied by remarkable functional changes of LSECs with 174 DEGs (156 upregulated and 18 downregulated genes). The functions of these DEGs were mainly enriched in the inflammatory reactions and immune responses. Nine specifically expressed hub genes were identified. Among them, CCL4 and ITGAX showed the most significant correlation with NASH, with AUROC of 0.77 and 0.86, respectively. The protein-protein interaction network, mRNA-miRNA interaction network, and ceRNA network were further predicted. Conclusion: LSECs show significant structural damage and functional changes in NASH. The LSEC-related DEGs, such as CCL4 and ITGAX, might be promising biomarkers as well as potential treatment targets for NASH.

| S-EPMC9533023 | biostudies-literature

Immunological functions of liver sinusoidal endothelial cells.

Project description:Liver sinusoidal endothelial cells (LSECs) line the liver sinusoids and separate passenger leukocytes in the sinusoidal lumen from hepatocytes. LSECs further act as a platform for adhesion of various liver-resident immune cell populations such as Kupffer cells, innate lymphoid cells or liver dendritic cells. In addition to having an extraordinary scavenger function, LSECs possess potent immune functions, serving as sentinel cells to detect microbial infection through pattern recognition receptor activation and as antigen (cross)-presenting cells. LSECs cross-prime naive CD8 T cells, causing their rapid differentiation into memory T cells that relocate to secondary lymphoid tissues and provide protection when they re-encounter the antigen during microbial infection. Cross-presentation of viral antigens by LSECs derived from infected hepatocytes triggers local activation of effector CD8 T cells and thereby assures hepatic immune surveillance. The immune function of LSECs complements conventional immune-activating mechanisms to accommodate optimal immune surveillance against infectious microorganisms while preserving the integrity of the liver as a metabolic organ.

| S-EPMC4856811 | biostudies-other

In hepatic fibrosis, liver sinusoidal endothelial cells acquire enhanced immunogenicity.

Project description:The normal liver is characterized by immunologic tolerance. Primary mediators of hepatic immune tolerance are liver sinusoidal endothelial cells (LSECs). LSECs block adaptive immunogenic responses to Ag and induce the generation of T regulatory cells. Hepatic fibrosis is characterized by both intense intrahepatic inflammation and altered hepatic immunity. We postulated that, in liver fibrosis, a reversal of LSEC function from tolerogenic to proinflammatory and immunogenic may contribute to both the heightened inflammatory milieu and altered intrahepatic immunity. We found that, after fibrotic liver injury from hepatotoxins, LSECs become highly proinflammatory and secrete an array of cytokines and chemokines. In addition, LSECs gain enhanced capacity to capture Ag and induce T cell proliferation. Similarly, unlike LSECs in normal livers, in fibrosis, LSECs do not veto dendritic cell priming of T cells. Furthermore, whereas in normal livers, LSECs are active in the generation of T regulatory cells, in hepatic fibrosis LSECs induce an immunogenic T cell phenotype capable of enhancing endogenous CTLs and generating potent de novo CTL responses. Moreover, depletion of LSECs from fibrotic liver cultures mitigates the proinflammatory milieu characteristic of hepatic fibrosis. Our findings offer a critical understanding of the role of LSECs in modulating intrahepatic immunity and inflammation in fibro-inflammatory liver disease.

| S-EPMC3119346 | biostudies-literature

Liver sinusoidal endothelial cells link hyperinsulinemia to hepatic insulin resistance.

Project description:Insulin signaling in vascular endothelial cells (ECs) is critical to maintain endothelial function but also to mediate insulin action on peripheral glucose disposal. However, gene knockout studies have reached disparate conclusions. Thus, insulin receptor inactivation in ECs does not impair insulin action, whereas inactivation of Irs2 does. Previously, we have shown that endothelial ablation of the three Foxo genes protects mice from atherosclerosis. Interestingly, here we show that mice lacking FoxO isoforms in ECs develop hepatic insulin resistance through excessive generation of nitric oxide (NO) that impairs insulin action in hepatocytes via tyrosine nitration of insulin receptors. Coculture experiments demonstrate that NO produced in liver sinusoidal ECs impairs insulin's ability to suppress glucose production in hepatocytes. The effects of liver sinusoidal ECs can be mimicked by NO donors and can be reversed by NO inhibitors in vivo and ex vivo. The findings are consistent with a model in which excessive, rather than reduced, insulin signaling in ECs predisposes to systemic insulin resistance, prompting a reevaluation of current approaches to insulin sensitization.

| S-EPMC3636600 | biostudies-literature

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