The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE172492 | GEO | 2022/04/07
REPOSITORIES: GEO
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Project description:The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver
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Project description:The purinergic P2Y14 receptor links hepatocyte death to hepatic stellate cell activation and fibrogenesis in the liver
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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.
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Project description:Hepatic stellate cells (HSCs) are the major driving factor in liver fibrosis. Upon liver inflammation caused by alcohol abuse and/or a fatty liver, HSCs transform from a quiescent- into a proliferating, fibrotic phenotype. We study this transformation termed “activation”, using state of the art TIMS-TOF mass spectrometry proteomics, as well as phenotype analysis of the immortalized LX-2 HSC cell line. In our work we employ a simple, yet reliable model of HSC activation via an in-crease in growth media serum concentration (serum activation). Protein network analysis of ac-tivated LX 2 cells reveals an increase in the production of ribosomal proteins and proteins related to migration. Interestingly, we could also observe a decrease in the expression of lipogenic pro-teins and a loss of cytosolic lipid droplets during activation. Especially the downregulation of proteins associated with cholesterol biosynthesis might be a promising target for further study. This work provides an update on HSC activation characteristics using contemporary proteomic and bioinformatic analysis and presents an accessible model for HSC activation.
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Project description:Activated hepatic stellate cells (HSC) that transdifferentiate to myofibroblasts in the injured liver are responsible for scar formation that leads to fibrosis and eventually cirrhosis. To investigate the gene expression profile during different stages of this process, we performed serial analysis of gene expression (SAGE), representing a quantitative and qualitative description of all expressed genes. Stellate cells were isolated from human livers and cultured. SAGE was performed on RNA isolated from quiescent, activated and transdifferentiated HSC. Comparison of the three resulting transcriptomes showed that less than 5% of all genes changed significantly in expression. Established markers of liver fibrosis showed enhanced expression in accordance with the transdifferentiation process. In addition, induction was seen for several genes not yet recognized to be involved in liver fibrosis, such as insulin-like growth factor binding proteins (IGFBP) and antagonists of bone morphogenic proteins: follistatin and gremlin. The induction of these genes was validated in vivo in mice developing liver fibrosis. The expression of IGFBPs and gremlin was measurable in the livers of these mice while it was low or undetectable in control mice without liver fibrosis. Since gremlin modulates the activity of bone morphogenic growth factors, it may represent a novel pathway and a target for therapeutic intervention and together with IGFBPs as a specific marker of liver fibrosis. In conclusion, the comparison of the three transcriptomes of (activated) stellate cells reveals novel genes involved in fibrogenesis and provides an appreciation of the sequence and timing of the fibrotic process in liver. Keywords: cell type comparison Human hepatic stellate cells (HSC) were isolated from wedge sections of normal human liver unsuitable for transplantation or from tumor-free human liver after partial hepatectomy as previously reported. Briefly, after a combined digestion with collagenase/pronase, HSC were separated from other liver nonparenchymal cells by ultracentrifugation over gradients of Larcoll (Sigma). The percentage of HSC in these isolates was > 90% as assessed by transmission microscopy, autofluorescence of vitamin A and immunofluorescence of vimentin. Immediately after isolation RNA was extracted for the construction of the SAGE library of quiescent HSC. To obtain activated stellate cells, these cells were cultured for 15 days on plastic culture dishes in modified Dulbecco's medium supplemented with 0.6 U/ml insulin, 2.0 mmol/L glutamine, 0.1 mmol/L nonessential amino acids, 1.0 mmol/L sodium pyruvate, antibiotic antifungal solution (Gibco) and 20% fetal bovine serum. To obtain fully transdifferentiated hepatic stellate cells, or myofibroblasts, the cells were cultured until they had reached passage 6 to 7. Myofibroblast phenotype was confirmed by detection of vimentin and ?-smooth muscle actin using immunofluorescence with monoclonal antibodies from Dako and Sigma, respectively. Medium was refreshed twice a week and at the indicated period RNA was extracted using Trizol (Quiagen)
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Project description:Background/Aims: Sept4, a subunit of the septin cytoskeleton specifically expressed in quiescent hepatic stellate cells (HSCs), is downregulated through transdifferentiation to fibrogenic and contractile myofibroblastic cells. Since Sept4?/? mice are prone to liver fibrosis, we examined the unknown molecular network underlying liver fibrosis by probing the association between loss of Sept4 and accelerated transdifferentiation of HSCs. Methods: We compared the transcriptomes of Sept4+/+ and Sept4?/? HSCs by differential DNA microarray analysis and quantitative RT-PCR. Based on reduced dickkopf2 (Dkk2) gene expression in Sept4?/? HSCs, we tested whether supplementing Dkk2 could suppress myofibroblastic transformation of Sept4?/? HSCs. We used a lymphoid enhancer-binding factor/transcription factor-luciferase reporter assay to test whether Dkk2 can exert anti-fibrotic effects by interfering with the canonical Wnt pathway. Results: We observed consistent upregulation of Dkk2 in primary cultured HSCs and in a carbon tetrachloride hepatitis model in mice, which decreased with loss of Sept4. Supplementing Dkk2 suppressed the induction of pro-fibrotic genes (?-smooth muscle actin and 2 collagen genes) and induced an anti-fibrotic gene (Smad7) in Sept4?/? HSCs. In human liver specimens with inflammation and fibrosis, Dkk2 immunoreactivity appeared to be positively correlated with the degree of fibrotic changes. Conclusions: Pro-fibrotic transformation of HSCs through the loss of Sept4 is partly due to reduced expression of Dkk2 and its homologues, and the resulting disinhibition of the canonical Wnt pathway. We induced Liver Cirrhosis to SEPT4-KO or wild type mouse by CCl4, and examined mRNA expression profiling in hepatic stellate cell of these mouse.
2012-06-02 | E-GEOD-24588 | biostudies-arrayexpress
Project description:Liver fibrosis, a consequence of chronic liver damage or inflammation, is characterized by the excessive buildup of extracellular matrix components. This progressive condition significantly raises the risk of severe liver diseases like cirrhosis and hepatocellular carcinoma. The lack of approved therapeutics underscores the urgent need for novel anti-fibrotic drugs. Hepatic stellate cells (HSCs), key players in fibrogenesis, are promising targets for drug discovery. This study investigated the anti-fibrotic potential of Citrus hystrix DC. (KL) and its bioactive compound, β-citronellol (β-CIT), in a human HSC cell line (LX-2). Cells exposed to TGF-β1 to induce fibro-genesis were co-treated with crude KL extract and β-CIT. Gene expression was analyzed by Re-al-Time qRT-PCR to assess fibrosis-associated genes (ACTA2, COL1A1, TIMP1, SMAD2). The re-leasing of matrix metalloproteinase 9 (MMP-9) was measured by ELISA. Proteomic analysis and molecular docking identified potential signaling proteins and modeled protein-ligand interac-tions. Results showed that both crude KL extract and β-CIT suppressed HSC activation genes and MMP-9 levels. The MAPK signaling pathway emerged as a potential target of β-CIT. This study demonstrates the potential of KL extract and β-CIT to inhibit HSC activation during TGF-β1-induced fibrogenesis, suggesting the promising role of β-CIT in anti-hepatic fibrosis therapies.
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Project description:Hepatic stellate cells are the primary cell type responsible for development of fibrosis in chronic liver disease. We used directional RNA sequencing (RNA-seq) and chromatin immunoprecipitation and sequencing (ChIP-seq) to identify the lncRNAs expressed in human HSCs. We also identified the lncRNAs that change in expression with differentiation of nonfibrotic quiescent HSCs into fibrotic HSC myofibroblasts and those that are regulated by TGF-beta signaling. ChIP-seq was also performed to identify DNA regions occupied by H3K27ac to define super-enhancers in HSC myofibroblasts. This study identified lncRNAs expressed HSCs that may regulate fibrosis. Analysis of genome-wide lncRNA expression using RNA-seq and ChiP-seq in human HSCs under four different conditions
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