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 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: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:Splenomegaly is caused by several pathological conditions, including portal hypertension, which is most frequently caused by chronic liver disease (e.g., liver cirrhosis). The detailed mechanisms through which portal pressure induces splenomegaly and the precise pathophysiological conditions in portal hypertension-induced splenomegaly remain to be fully elucidated. We used microarrays to identify the differential microRNA expression underlying the portal hypertension-induced splenomegaly.
2018-11-21 | GSE113612 | GEO
Project description:Splenomegaly is caused by several pathological conditions, including portal hypertension, which is most frequently caused by chronic liver disease (e.g., liver cirrhosis). The detailed mechanisms through which portal pressure induces splenomegaly and the precise pathophysiological conditions in portal hypertension-induced splenomegaly remain to be fully elucidated. We used microarrays to identify the differential gene expression underlying the portal hypertension-induced splenomegaly.
2018-11-21 | GSE113613 | GEO
Project description:Persistent liver injury triggers a fibrogenic program that causes pathologic remodelling of the hepatic microenvironment (i.e., liver fibrosis) and portal hypertension. The dynamics of gene regulation during liver disease progression and regression remain understudied. Here, we generated hepatic transcriptome profiles in two well-established liver disease models at peak fibrosis and during spontaneous regression after the removal of the inducing agents. We linked the dynamics of key liver disease readouts, such as portal pressure, collagen proportionate area, and transaminase serum levels, to most differentially expressed genes, enabling the identification of transcriptomic signatures of progressive vs. regressive liver fibrosis and portal hypertension. These candidate biomarkers (e.g., Scube1, Tcf4, Src, Hmga1, Trem2, Mafk, Mmp7) were also validated in RNA-seq datasets of patients with cirrhosis and portal hypertension. Finally, deconvolution analysis identified major cell types and suggested an association of macrophage and portal hepatocyte signatures with portal hypertension and fibrosis area in both models.
2024-02-13 | E-MTAB-13804 | biostudies-arrayexpress
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:Abstract: Background and aims: Portal hypertension (PH) is the most frequent and severe clinical syndrome associated to chronic liver disease (CLD), defined by a pathological increase in the hepatic venous pressure gradient (HVPG). Considering the known mechanobiological effects of hydrostatic pressure and shear stress on endothelial cells, we hypothesized that PH could not only be a consequence of, but significantly influence the phenotype of liver sinusoidal endothelial cells (LSECs) during disease progression. The aim of this study was to investigate the effects of pathological hydrodynamic pressure on LSECs and to identify endothelial-derived biomarkers of PH. Methods: Primary LSECs were cultured under normal or increased hydrodynamic pressure within a pathophysiological range (1 vs 12 mmHg) using a microfluidic liver-on-a-chip device. RNAseq was used to identify pressure-sensitive genes, which were validated in liver biopsies from two independent cohorts of CLD patients with PH (n=73) vs subjects without PH (n=23). Biomarker discovery was performed in plasma from a third independent cohort of 64 patients (46 with PH vs 18 w/o). Results: Transcriptomic analysis revealed a marked deleterious effect of pathological pressure in LSECs and identified chromobox 7 (CBX7) as a key transcription factor diminished by pressure. Hepatic CBX7 downregulation was validated in patients with PH and significantly correlated with HVPG. MicroRNA 181a-5p was identified as pressure-induced upstream regulator of CBX7. Analysis of two downstream targets of CBX7, ECAD and SPINK1, were found increased in the bloodstream of patients with PH and were highly predictive of PH and clinically significant PH, with a sensitivity of 91.3% and 91.4% respectively. Conclusions: We describe the detrimental effects of increased hydrodynamic pressure on the sinusoidal endothelium, identify CBX7 as a pressure-sensitive transcription factor, and propose that the combination of two of its reported products could be used as plasma biomarkers of PH.
2023-05-10 | GSE181255 | GEO
Project description:Background & Aims: NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSECs-expressed POFUT1 in liver fibrosis. Methods: Endothelial-specific Pofut1 knockout mice were generated and subjected to experimental liver fibrosis by chronic carbon tetrachloride exposure or by common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA-seq, qPCR, and Western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSECs cultures. Liver single-cell RNA-seq data sets from cirrhotic patients and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. Results: POFUT1 loss promoted injury-induced LSECs capillarization and HSC activation, leading to aggravated liver fibrosis. RNA-seq analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of cirrhotic patients. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to treatment with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling. Conclusions: Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen which function as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/NOTCH/HES1/STAT3/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases.
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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: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