Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release in a spatial manner to amplify liver fibrosis
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ABSTRACT:
PROVIDER: PRJNA1081368 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28129105_1.fastq.gz | Fastqsanger.gz | |||
| SRR28129105_2.fastq.gz | Fastqsanger.gz | |||
| SRR28129106_1.fastq.gz | Fastqsanger.gz | |||
| SRR28129106_2.fastq.gz | Fastqsanger.gz | |||
| SRR28129107_1.fastq.gz | Fastqsanger.gz |
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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: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:Effect of glycolysis on hepatic stellate cell transcriptome
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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: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:Hepatic stellate cell autophagy inhibits extracellular vesicle release to attenuate liver fibrosis. Primary human hepatic stellate cells were treated with PDGF or PDGF + SHP2 inhibitor. RNA was purified and submitted for sequencing to Mayo Clinic Genomics Core. After applying the filters FDR>0.05, Log2(FC)>1 and RPKM>15, we ended up with nearly 300 genes differentially regulated between the two conditions. Ingenuity Pathway Analysis revealed that Ostheoarthritis was the first pathway to be differentially regulated. From this pathway, REDD1 (DDIT4 transcript), an mTOR inhibitor, was further explored, especially in the context of extracellular vesicle release.
2019-11-08 | GSE140110 | GEO
Project description:Gene-expression profiles of hepatic stellate cells isolated from IL15R-alpha knockout mouse IL-15 and its high affinity receptor IL-15Rα are widely expressed in immune cells including dendritic cells and macrophages and non-immune cells such as hepatocytes, oval cells and hepatic stellate cells (HSC). IL-15 signaling has important functions in natural killers (NK), natural killers T (NKT) and cytotoxic T (CD8+T) cell homeostasis and also in liver regeneration. We hypothesized that IL-15 may have a protective role during liver fibrosis progression due to its role in NK cell homeostasis. We compared fibrosis progression in IL-15Rα knockout mice (IL-15RαKO) to wild type mice using two mechanistically distinct models, chronic carbon tetrachloride (CCl4) exposure and bile duct ligation (BDL). Enhanced fibrosis progression was observed in IL-15RαKO mice in both models. Furthermore, using congenic bone marrow transplantation (BMT), we demonstrated an unexpected role for IL-15 signaling in hepatic resident cells for the maintenance of liver NK and CD8+T cell populations. Using this approach, transplanting IL-15RKO hematopoietic cells results in NK defect that surprisingly is not reflected in a change of fibrosis progression. However, chimeric mice with defect of IL-15R on liver resident cells have similar NK defects and significant more fibrosis after CCL4 liver injury. This supports a direct protective, anti-fibrogenic role for IL-15R on one of the radioresistant liver cell populations (hepatocytes, HSC and sessile Kupffer cells). Microarray analysis of IL15RKO HSC suggests up-regulation of collagen transcripts and down-regulation of pathways involved in cell proliferation/survival. Finally, activated HSCs isolated from IL-15RKO mice show increased collagen secretion and as predicted, no changes in the growth curves. In summary, IL-15Rα signaling has an anti-fibrotic effect through both BM-derived and hepatic resident cells. These findings establish a rationale to explore IL-15 signaling in HSC as a potential therapeutic target in liver fibrogenesis.
2016-09-21 | GSE45612 | GEO
Project description:A novel deactivation factor of fibrogenic hepatic stellate cells induces regression of liver fibrosis in mice
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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