GIMAP5 maintains liver sinusoidal endothelial cell identity and prevents portal hypertension
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE158988 | GEO | 2021/03/01
REPOSITORIES: GEO
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Project description:Background & Aims Congestion alters the microenvironment of the liver sinusoid along the portal-central axis. We studied spatial changes in immune cells in the sinusoid which contribute to congestive fibrosis and portal hypertension (PHTN). Methods To visualize the distribution of immune cells in congestive hepatopathy (CH), we performed imaging mass cytometry (IMC) on liver tissue from patients with CH, Fontan-associated liver disease (FALD), and controls. We performed partial ligation of the inferior vena cava (pIVCL) to simulate CH in mice and isolated primary liver cells for single cell RNA-sequencing (scRNA-seq) to study zonation of liver sinusoidal endothelial cells (LSECs). After pIVCL, mice were treated with intraperitoneal injections of AMG487, an inhibitor of the CXCL9 receptor. Results Peri-central macrophages are enriched in CH and FALD. Given the role of CXCL9 in macrophage patterning in the liver, we performed RNA in situ hybridization (RNAish) in CH and determined that CXCL9 was highly expressed in LSECs in FALD, suggesting that LSECs recruit macrophages in CH. After pIVCL, treatment with AMG487 attenuated portal pressures, fibrosis, and intra-hepatic macrophages. To study changes in LSECs which promote macrophage chemotaxis, we performed scRNA-seq after pIVCL and sham procedures. Analysis revealed 3 LSEC subpopulations according to sinusoidal location. RNANish identified peri-central LSECs as the predominant source of CXCL9 in FALD. In vitro analyses revealed that -catenin and hypoxia inducible factor-1α regulate CXCL9 transcription in peri-central LSECs. Conclusions CXCL9 derived from peri-central LSECs enriches intra-hepatic macrophages in CH and FALD, contributing to congestive fibrosis and PHTN. Strategies to target LSEC-derived CXCL9 may prevent the progression of CH and FALD.
2024-01-27 | GSE253915 | GEO
Project description:Background and aims. Portal hypertension is the main consequence of cirrhosis, responsible for the complications defining clinical decompensation. The only cure for decompensated cirrhosis is liver transplantation, but it is a limited resource and opens the possibility of regenerative therapy. We investigated the potential of human amniotic membrane-derived mesenchymal stromal (hAMSCs) and epithelial (hAECs) stem cells for the treatment of portal hypertension and chronic liver disease. Methods. In vivo: hAMSCs and hAECs were isolated from human amniotic membranes. Cirrhotic rats with ascites (chronic CCl4 inhalation) received 4x10e6 hAMSCs, 4x10e6 hAECs, or vehicle (NaCl 0.9%) (intraperitoneal; n=10 per group). After 2-week we analyzed: a) portal pressure (PP) and liver microcirculatory function; b) liver sinusoidal endothelial (LSECs) and hepatic stellate (HSCs) cells phenotype; c) hepatic fibrosis, inflammation and hepatic function. In vitro: HSCs isolated from CCl4-cirrhotic rats were co-cultured with hAMSCs, hAECs or vehicle for 24h. RNA profile was analyzed by RNAseq. Results. Cirrhotic rats receiving hAMSCs or hAECs had significantly lower PP than vehicle-treated animals, together with improved liver microcirculatory function. This hemodynamic amelioration was associated with improvement in LSECs capillarization and HSCs de-activation, although hepatic collagen/fibrosis was not significantly reduced. Rats that received placenta derived stem cells had markedly reduced hepatic inflammation and oxidative stress. Finally, liver function tests significantly improved in rats receiving hAMSCs. In vitro experiments confirmed HSCs de-activation when co-cultured with stem cells. Conclusion. This pre-clinical study shows that infusion of human amniotic stem cells effectively decreases PP by ameliorating liver microcirculation, suggesting that it may represent a new treatment option for advanced cirrhosis with portal hypertension.
2021-09-11 | GSE125955 | GEO
Project description:Portal hypertension (PHTN) is a severe complication of liver cirrhosis. It is associated with intrahepatic sinusoidal remodeling induced by sinusoidal resistance and angiogenesis. Collagen type IV (COL4), a major component of basement membrane (BM), forms in liver sinusoids upon chronic liver injury. However, the cellular source and transcriptional regulation of COL4, as well as how it progresses in liver diseases is unknown. Here, we examined how COL4 is produced and how it regulates sinusoidal remodeling in PHTN. RNA-seq analysis on human cirrhotic livers revealed an increase in COL4 expression, which was further confirmed via immunofluorescence (IF) staining. scRNA-seq analysis identified Liver sinusoidal endothelial cells (LSECs) as the predominant source of COL4 expression in mouse liver, which was upregulated in a TNFα-NFκB dependent manner. Epigenetic repression of enhancer-promoter interaction silences COL4 gene expression via dCas9-KRAB-mediated epigenome editing approach. LSEC-specific COL4 mutation or repression abrogated sinusoidal resistance and angiogenesis, thereby alleviated sinusoidal remodeling and PHTN. Our findings reveal LSECs as a major source of COL4 in the liver which plays a prominent role in sinusoidal remodeling and PHTN.
2024-01-01 | GSE233284 | GEO
Project description:Disturbance of heterologous cell communication is associated with a structural reorganization of the vascular niche, a process called capillarization, which is already initiated in early stages of liver tumor development. In this study, the molecular characterization of endothelial cell (EC) subpopulations from healthy livers and yes-associated protein (Yap)-induced liver tumors revealed a dynamic crosstalk between liver sinusoidal endothelial cells (LSECs) and capillary endothelial cells (CECs). Initial paracrine stimuli from parenchymal cells include the Yap/Tead4 target gene osteopontin (Opn), which promotes CECs expansion through the induction of c-Met and sensitization towards LSEC-derived hepatocyte growth factor (Hgf). In addition, Yap/Tead4-induced C-C motif chemokine ligand 2 (Ccl2) recruits bone-marrow-derived macrophages (BMDMs) with an unpolarized phenotype (M0) to the perivascular space of expanding CECs.
2020-09-15 | GSE128046 | GEO
Project description:Disturbance of heterologous cell communication is associated with a structural reorganization of the vascular niche, a process called capillarization, which is already initiated in early stages of liver tumor development. In this study, the molecular characterization of endothelial cell (EC) subpopulations from healthy livers and yes-associated protein (Yap)-induced liver tumors revealed a dynamic crosstalk between liver sinusoidal endothelial cells (LSECs) and capillary endothelial cells (CECs). Initial paracrine stimuli from parenchymal cells include the Yap/Tead4 target gene osteopontin (Opn), which promotes CECs expansion through the induction of c-Met and sensitization towards LSEC-derived hepatocyte growth factor (Hgf). In addition, Yap/Tead4-induced C-C motif chemokine ligand 2 (Ccl2) recruits bone-marrow-derived macrophages (BMDMs) with an unpolarized phenotype (M0) to the perivascular space of expanding CECs.
2020-09-15 | GSE128045 | GEO
Project description:Disturbance of heterologous cell communication is associated with a structural reorganization of the vascular niche, a process called capillarization, which is already initiated in early stages of liver tumor development. In this study, the molecular characterization of endothelial cell (EC) subpopulations from healthy livers and yes-associated protein (Yap)-induced liver tumors revealed a dynamic crosstalk between liver sinusoidal endothelial cells (LSECs) and capillary endothelial cells (CECs). Initial paracrine stimuli from parenchymal cells include the Yap/Tead4 target gene osteopontin (Opn), which promotes CECs expansion through the induction of c-Met and sensitization towards LSEC-derived hepatocyte growth factor (Hgf). In addition, Yap/Tead4-induced C-C motif chemokine ligand 2 (Ccl2) recruits bone-marrow-derived macrophages (BMDMs) with an unpolarized phenotype (M0) to the perivascular space of expanding CECs.
2020-09-15 | GSE128044 | GEO
Project description:Disturbance of heterologous cell communication is associated with a structural reorganization of the vascular niche, a process called capillarization, which is already initiated in early stages of liver tumor development. In this study, the molecular characterization of endothelial cell (EC) subpopulations from healthy livers and yes-associated protein (Yap)-induced liver tumors revealed a dynamic crosstalk between liver sinusoidal endothelial cells (LSECs) and capillary endothelial cells (CECs). Initial paracrine stimuli from parenchymal cells include the Yap/Tead4 target gene osteopontin (Opn), which promotes CECs expansion through the induction of c-Met and sensitization towards LSEC-derived hepatocyte growth factor (Hgf). In addition, Yap/Tead4-induced C-C motif chemokine ligand 2 (Ccl2) recruits bone-marrow-derived macrophages (BMDMs) with an unpolarized phenotype (M0) to the perivascular space of expanding CECs.
2020-09-15 | GSE128042 | GEO
Project description:Liver sinusoidal endothelium (LSEC) is a prime example for organ-specific microvascular differentiation and functions. Disease-associated capillarization of LSEC in vivo and dedifferentiation of LSEC in vitro indicate the importance of the hepatic microenvironment. To identify the LSEC-specific molecular differentiation program in the rat, we used a two-sided gene expression profiling approach comparing LSEC freshly isolated ex vivo with both lung microvascular endothelial cells (LMEC) and with LSEC cultured for 42h. The LSEC signature consisted of 48 genes both down-regulated in LMEC and in LSEC upon culture (FC>7 in at least one comparison); qRT-PCR confirmation of these genes included numerous family members and signalling pathway-associated molecules. The LSEC differentiation program comprised distinct sets of growth (wnt2, Fzd4, 5, 9, wls, VEGFR1, 2, 3, Nrp2) and transcription factors (Gata4, Lmo3, Tcfec, Maf) as well as endocytosis-related (Stabilin-1/2, Lyve1 and Ehd3) and cytoskeleton-associated molecules (Rnd3/RhoE). Specific gene induction in cultured LSEC versus freshly isolated LSEC as well as LMEC (Esm-1, Aatf) and up-regulation of gene expression to LMEC levels (CXCR4, Apelin) confirmed true transdifferentiation of LSEC in vitro. In addition, our analysis identified a novel 26 kDa single-pass transmembrane protein, liver endothelial differentiation-associated protein (Leda)-1, that was selectively expressed in all liver endothelial cells and preferentially localized to the abluminal cell surface. Upon forced over-expression in MDCK cells, Leda-1 was sorted baso-laterally to E-cadherin-positive adherens junctions suggesting functional involvement in cell adhesion and polarity. Conclusion: Comparative microvascular analysis in rat identified a hepatic microenvironment-dependent LSEC-specific differentiation program including the novel junctional molecule Leda-1. Highly pure liver sinusoidal endothelial cells (LSEC) and lung microvascular endothelial cells (LMEC) were isolated by enzymatic digestion, density gradient centrifugation and MACS sorting and subjected to RNA extraction and affymetrix hybridization without any culturing step (LSEC_0h, LMEC_0h). LSEC were also plated on collagen coated dishes and RNA extraction and Affymetrix hybridization was carried out after 2h and 42h in culture (LSEC_2h, LSEC_42h).
2010-05-05 | E-GEOD-20375 | biostudies-arrayexpress
Project description:Liver sinusoidal endothelial cells (LSECs) are specialized fenestrated scavenger endothelial cells involved in the elimination of modified plasma proteins and tissue turnover waste macromolecules from blood. LSECs also participate in liver immune responses. A challenge when studying LSEC biology is the rapid loss of the in vivo cell phenotype in culture. In this study, we have examined biological processes and pathways affected during early-stage primary culture of rat LSECs and checked for cell responses to the pro-inflammatory cytokine interleukin (IL)-1 and the anti-inflammatory drug dexamethasone. Methods: LSECs from male Sprague Dawley rats were cultured on type I collagen in a 5% oxygen atmosphere in DMEM with serum-free supplements for 2 and 24 h. Quantitative proteomics using tandem mass tag technology were used to examine proteins in cells and supernatants. Validation was done with ELISA and multiplex immunobead assays, cell ultrastructure was examined by scanning electron microscopy, and scavenger function by quantitative endocytosis assays. Results: LSECs cultured for 24 h showed a characteristic pro-inflammatory phenotype both in the presence and absence of IL-1, displaying upregulation of cellular responses to cytokines and interferon-, cell-cell adhesion, and glycolysis, and downregulation of membrane/endocytosis receptors (MCAM, STAB1, STAB2, LYVE1, CLEC4G) and proteins involved in pyruvate metabolism, citric acid cycle, fatty acid elongation, amino acid metabolism, and oxidation-reduction processes. Dexamethasone improved LSEC viability in culture and repressed the culture-induced stimulation of glycolysis, inflammatory and immune regulatory pathways, and secretion of pro-inflammatory cytokines while increasing IL-10 secretion compared to time-matched control. The number of sieve plates in LSECs was reduced at 24 h both in the presence and absence of dexamethasone but the dexamethasone-treated cells showed a more quiescent phenotype. Conclusion: Rat LSECs become activated towards a pro-inflammatory phenotype during early culture. Dexamethasone represses LSEC activation and improves cell viability.
2022-09-06 | PXD029241 | Pride
Project description:Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) have important roles in liver homeostasis and host defense. Sharing the same microenvironment in the liver sinusoid, they form an effective scavenger cell system for removal of potentially harmful blood-borne substances. Unlike most other endothelia, LSECs are highly efficient in endocytosis of nanoparticles, including virus. Though controversial, LSECs have been reported to act as antigen presenting cells, thus contributing importantly to induction of immune tolerance in liver. There are also controversies about LSEC and KC specific markers, which may be due to overlapping cell functions, species differences, and/or problems with cell purification. We therefore used label-free proteomics to characterize and quantitatively compare proteome of freshly isolated, highly pure rat LSECs (SE-1/CD32b positive) and KCs (CD11b/c positive.We found that most immune genes expressed in KCs were also expressed in LSECs, albeit at a lower density, and they also have overlap in cell surface marker expression. Both cell types express high levels of scavenger receptors and immune lectins.
2020-11-11 | PXD012080 | Pride