A novel deactivation factor of fibrogenic hepatic stellate cells induces regression of liver fibrosis in mice
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ABSTRACT:
PROVIDER: PRJNA529232 | ENA |
REPOSITORIES: ENA
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Project description:It has been reported that hepatic stellate cells (HSCs) differentiate from mesodermal-derived submesothelial cells during embryonic development, and that these cells express a common surface marker p75 neurotrophin receptor (p75NTR). We sorted p75NTR-expressing cells in embryonic liver at each developmental stage, and transcription profiles were analyzed using the DNA microarray.
2019-09-27 | GSE128895 | GEO
Project description:Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nano-sized extracellular vesicles (EVs) and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated upregulation of EV-related pathways in the liver pericentral zone, which was abrogated by the glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs upregulated the expression of EV-related genes such as RAB31 by enhancing histone-3-lysine-9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
2024-05-16 | PXD050337 | Pride
Project description:Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs) and the release of fibrogenic nano-sized extracellular vesicles (EVs). Activated HSCs increase their glucose metabolism via glycolysis to satisfy high energy demands. Nevertheless, the mechanism of how glycolysis in HSCs coordinates fibrosis amplification in the fibrogenic zones in the liver is elusive and is the scope of this study. Single cell RNA sequencing (scRNAseq) and bulk RNAseq demonstrated that several glycolysis enzymes, including hexokinase 2 (HK2), were upregulated in activated HSCs. HSC-selective glycolysis-deficient mice (HK2ΔHSC) showed abrogated CCl4-mediated fibrosis as compared to littermate controls (HK2fl/fl). Spatial transcriptomics revealed an upregulation of several EV-related pathways in the fibrotic pericentral zone during liver fibrosis in control HK2fl/fl mice. However, glycolysis-deficient HK2ΔHSC mice showed downregulation of these EV-related pathways in the pericentral zone. Consistently, induction of glycolysis in HSCs in vitro, either by glucose or platelet-derived growth factor B (PDGF), upregulated the expression of several extracellular vesicle (EV)-related genes, including RAB31. Glycolysis in HSCs epigenetically enhanced RAB31 expression through histone-3 lysine-9 acetylation (H3K9ac) on the promoter region, leading to increased EV release. Functionally, glycolysis-dependent EVs were enriched with fibrogenic molecules and increased the expression of fibrotic markers in recipient HSCs. Finally, EVs derived from glycolysis-deficient HK2ΔHSC mice abrogated liver fibrosis amplification as compared to EVs derived from littermate control HK2fl/fl mice. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the pericentral fibrotic regions in the liver.
2024-03-20 | GSE259363 | GEO
Project description:In response to liver injury, hepatic stellate cells activate and acquire proliferative and contractile features. The regression of liver fibrosis appears to involve the clearance of activated hepatic stellate cells, either by apoptosis or by reversion toward a quiescent-like state, a process called deactivation. Thus, deactivation of active hepatic stellate cells has emerged as a novel and promising therapeutic approach for liver fibrosis. However, our knowledge of the master regulators involved in the deactivation and/or activation of fibrotic hepatic stellate cells is still limited. The transcription factor GATA4 has been previously shown to play an important role in embryonic hepatic stellate cell quiescence. In this work, we show that lack of GATA4 in adult mice caused hepatic stellate cell activation and, consequently, liver fibrosis. During regression of liver fibrosis, Gata4 was reexpressed in deactivated hepatic stellate cells. Overexpression of Gata4 in hepatic stellate cells promoted liver fibrosis regression in CCl4-treated mice. GATA4 induced changes in the expression of fibrogenic and antifibrogenic genes, promoting hepatic stellate cell deactivation. Finally, we show that GATA4 directly repressed EPAS1 transcription in hepatic stellate cells and that stabilization of the HIF2α protein in hepatic stellate cells leads to liver fibrosis.
| S-EPMC8675192 | biostudies-literature
Project description:In order to identify novel transcription target genes of COUP-TFII that could account for the fibrogenic phenotype of human hepatic stellate cells (HSCs), we carried out an exploratory microarray analysis with mRNA extracted from cultured HSC transfected with COUP-TFII wt or control plasmid.
2014-02-01 | E-MTAB-1795 | biostudies-arrayexpress
Project description:Gene expression of hepatic stellate cells exposed to fetal bovine serum (FBS) (cultured alone and in the presence of Kupffer cells) activated and CCl4 exposure and Bile-duct ligation is characterized. Affymetrix Mouse 430 2.0 gene expression measurements were used to characterize the transcriptomic basis of the effects of the above treatments and genotypes on firbrogenesis. Gene expression of mouse hepatic stellate cells was characterized under the following conditions: A. Quiescent (n=5). B. Activated by FBS (n=3). C. Cocultured with Kupffer cells and activated by FBS (n=3). D. Activate by bile-duct ligation (n=3). E. Activated by CCl4 (n=3).
2014-12-19 | E-GEOD-34640 | biostudies-arrayexpress
Project description:Gene expression of mouse hepatic stellate cells was characterized under the following conditions: Quiescent (isolated from normal mouse liver) and reverted (isolated from mouse liver treated with 4 injections of carbontetrachloride followed by 45 day rest period) Affymetrix Mouse 1.0ST gene expression measurements were used to characterize the transcriptomic basis in quiescent hepatic stellate cells, isolated from normal liver, and reverted hepatic stellate cells, isolated from liver treated with 4 injections of CCl4 followed by a 45 day rest period. Gene expression of mouse hepatic stellate cells was characterized under the following conditions: A. Quiescent control hepatic stellate cells (n=4). B. Reverted hepatic stellate cells (n=4).
2014-05-05 | E-GEOD-38648 | biostudies-arrayexpress
Project description:Liver injury causes “transdifferentiation” of quiescent hepatic stellate cells (Q-HSCs) into wound repairing myofibroblasts (MF-HSCs), whose uncontrolled activation leads ultimately to liver fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, using a compendium of in vitro, ex vivo and in vivo models of fibrogenic liver injuries in addition to human liver samples, we report that O-linked β D N acetylglucosaminylation (O GlcNAcylation), a post-translational modification (PTM) considered as nutritional sensor, is increased during myofibroblastic activation of HSCs and is required for their pro-fibrotic activities. Mechanistically, a multi omics approach combining proteomic, epigenomic and transcriptomic data mining revealed that O GlcNAcylation controls the transcriptional program of MF-HSCs by targeting the key fibrogenic transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of fibrogenic transcriptional regulatory elements. Altogether, this study unravels the fibrogenic role of protein O-GlcNAcylation identifying a vulnerable regulatory process in activated HSCs.
2024-05-21 | PXD045860 | Pride
Project description:Development of liver fibrosis is associated with activation of quiescent Hepatic Stellate Cells (qHSCs) into Collagen Type I-producing myofibroblasts (aHSCs). Cessation of liver injury often results in fibrosis resolution and inactivation of aHSCs/myofibroblasts into a quiescent-like state (iHSCs). To identify the molecular drivers of these HSC phenotypes, we investigated the global gene expression and epigenetic changes in H3K4me2 and H3K27ac marks of primary murine and human HSCs. Motif enrichment identified ETS1/2, GATA4/6, and IRF1/2 transcription factors (TFs) as putative regulators of the HSC lineage identity in murine and human HSCs. shRNA-knockdown of these TFs resulted in marked upregulation of fibrogenic and inflammatory genes and a loss of HSC-specific phenotype in targeted murine HSCs. In support, in vivo HSC-specific ablation of GATA4, GATA6, and ETS1, and ETS1 target genes NF1 (neurofibromin 1) and PPARγ exacerbated development of carbon tetrachloride (CCl4)-induced liver fibrosis in LratΔGATA6, LratETS1+/-, LratΔNF1, and LratΔPPARγ mice (vs wt littermates), but only LratΔGATA6, and LratΔPPARγ mice exhibited a defect in fibrosis resolution due to the lack of HSC inactivation. Therapeutic administration of a PPARγ agonist accelerated regression of liver fibrosis in CCl4-induced wt, but not in LratΔPPARγ mice, suggesting that PPARγ signaling in HSCs is critical for HSC inactivation and regression of liver fibrosis. Common transcription factors determine the phenotype of mouse and human HSCs. Similar to murine HSCs, human aHSCs can revert into a quiescent-like, inactivated phenotype. GATA4, GATA6, and PPARγwere identified as an important driver of human HSC inactivation.
2020-01-27 | GSE140641 | GEO
Project description:The p53 protein is a cell-autonomous tumor suppressor that restricts malignant transformation by triggering cell cycle exit or apoptosis. p53 also promotes cellular senescence, a program that triggers a stable cell cycle arrest and can modify the tissue microenvironment through its effect on cell membrane and secretory proteins. Here we show that specific ablation of p53 in hepatic stellate cells, which undergo a process of proliferation and senescence in the fibrogenic response to liver damage, enhances liver cirrhosis, reduces survival and increases the malignant transformation of adjacent epithelial cells into hepatocellular carcinoma. This p53-dependent senescence program involves the release of secreted proteins which skew macrophages into a tumor-inhibiting M1-state that can eliminate senescent stellate cells. In contrast, p53-deficient stellate cells secrete factors that promote M2 polarization, which is pro-tumorigenic. Our study reveals that p53 can exert a non-cell-autonomous tumor suppressor response and suggests that this occurs, in part, by its ability to influence macrophage polarization. We used microarrays to detail the global programme of gene expression underlying p53-dependent senescent and identified distinct classes of up-regulated or down-regulated genes during this process. Proliferating and senescent stellate cell pellets were collected RNA extraction and hybridization on Affymetrix microarrays.
2013-04-05 | E-GEOD-39469 | biostudies-arrayexpress