Gene expression during primary Hepatic Stellate Cells activation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE322502 | GEO | 2026/03/05
REPOSITORIES: GEO
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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.
2024-05-16 | PXD050337 | Pride
Project description:Unveiling the regulatory pathways maintaining hepatic stellate cells (HSC) in a quiescent (q) phenotype is essential to develop new therapeutic strategies to treat fibrogenic diseases. To uncover the miRNA-mRNAs regulatory interactions in qHSCs, HSCs were FACS-sorted from healthy livers and activated HSCs were generated in vitro. MiRNA Taqman array analysis showed HSCs expressed a low number of miRNA, from which 46 were down-regulated and 212 up-regulated upon activation. Computational integration of miRNA and gene expression profiles revealed that 66% of qHSCs miRNAs correlated with more than 6 altered targeted mRNAs (17,28±10,7 targets/miRNA), whereas aHSC-associated miRNAs had an average of 1,49 targeted genes. Interestingly, interaction networks generated by miRNA-targeted genes in qHSCs were associated with key HSCs activation processes. Next, selected miRNAs were validated in healthy and cirrhotic human livers and miR-192 was chosen for functional analysis. Down-regulation of miR-192 in HSC was found to be an early event during fibrosis progression in mouse models of liver injury. Moreover, mimic assays for miR-192 in HSCs revealed its role in HSC activation, proliferation and migration. Together, these results uncover the importance of miRNAs in the maintenance of qHSC phenotype and form the basis for understanding the regulatory networks in HSCs. Transcriptomic profile derived from four quiescent hepatic stellate (QHSC), four activated hepatic stellate (AHSC), three liver sinusoidal endothelial (LSEC) and two hepatocytes cells (HEP).
2015-11-23 | E-GEOD-67664 | biostudies-arrayexpress
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:Aims: To obtain small non-coding RNA expression profiles of short-term activated and long-term activated hepatic stellate cells (HSCs). To obtain small non-coding RNA expression profiles of small extracellular vesicles (sEVs) from short-term activated and long-term activated HSCs. Methods: Primary rat HSCs were isolated and cultured in vitro. To isolate HSC-derived sEVs, culture media (CMs) from Day 0 to Day 3 and Day 7 to Day 14 were collected. The sEVs from Day 0 to Day 3 HSC CMs were referred to as short-term activated HSC-sEVs (3dHSC-sEVs), and those from Day 7 to Day 14 HSC CMs were referred to as long-term activated HSC-sEVs (14dHSC-sEVs). Day 3 HSCs, Day 14 HSCs, and HSC-sEVs were collected and lysed in TRIzol (Life Technologies) for RNA sample preparation at the indicated time points.
2024-08-29 | E-MTAB-12764 | biostudies-arrayexpress
Project description:Activation and migration of hepatic stellate cells (HSCs) followed by matrix deposition are characteristics of liver fibrosis. Several studies have shown the importance of hepatocyte and endothelial cell-derived extracellular vesicles (EVs) in liver pathobiology. However, less is known about the role of HSC-derived EVs in liver diseases. In this study, we investigated the molecules released through HSC-derived EVs and whether these can promote fibrosis.
2018-10-18 | PXD007258 | Pride
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:BACKGROUND AND AIM: We previously established that endoplasmic reticulum stress leads to unfolded protein response (UPR) that promotes liver fibrosis by activating hepatic stellate cell (HSC). We aimed to determine the role of X-box binding protein 1 (XBP1), one of three UPR effector pathways, in the fibrogenic HSC activation. METHODS: XBP1 expression was measured by qPCR in tunicamycin-treated human HSC lines (TWNT4 and LX2) and culture-activated human primary HSCs. XBP1 was overexpressed in primary human HSCs and the HSC lines, and fibrogenic genes (COL1A1, ACTA2, PDGFRB, MMP2, TIMP1) and encoded proteins were assessed by qPCR and Western blotting, respectively. Autophagy was inhibited by knockdown of ATG7. Genome-wide transcriptome profiling was performed to determine modulated molecular pathway by XBP1. In vivo XBP1 activation was assessed in transcriptome datasets of fibrotic mouse models and immunohistochemistry of human liver tissues. RESULTS: XBP1 overexpression accompanied both tunicamycin- and culture-based HSC activation. Ectopic overexpression of XBP1 induced fibrogenic gene expression in the HSC lines, which was inhibited by knockdown of ATG7. UPR pathway together with PDGFRB pathway, a hallmark of HSC activation, were induced in transcriptome profiles of XBP1-transduced HSC lines. Some known fibrogenic pathways such as transforming growth factor (TGF)-beta pathway were not induced, suggesting partial contribution of XBP1 to the entire fibrogenic HSC activation machinery. XBP1 target gene signature defined in our XBP1-overexpressing HSC lines was significantly induced in liver tissue transcriptome profiles of carbon tetrachloride-treated or bile duct-ligated mouse models, and XBP1 and alpha-smooth muscle actin (encoded by ACTA2, another hallmark of HSC activation) were co-localized in human fibrotic liver tissues, collectively supporting involvement of XBP1 in HSC activation and fibrogesis in vivo. CONCLUSIONS: XBP1-mediated UPR is at least partially responsible for fibrogenic HSC activation via autophagy.
2016-12-21 | GSE78070 | GEO
Project description:This study aims to characterize the RNA editome during fibrogenesis and to elucidate the role of ADAR1 in hepatic stellate cell (HSC) activation and liver fibrosis. We showed that ADAR1 ablation in primary mouse HSCs ameliorated HSC activation. Mechanistically, ADAR1 ablation led to dsRNA accumulation and activated HSC-intrinsic IFN signaling in an MDA5-dependent manner. RNA editome analysis revealed that the 3’ UTR of the pro-fibrogenic gene Col3a1 was highly edited by ADAR1, leading to mRNA stabilization and increased protein expression. Targeting ADAR1-mediated RNA editing in HSCs holds promise to prevent and treat liver fibrosis.
2026-01-23 | GSE283569 | GEO
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.
2022-02-14 | PXD029121 | Pride
Project description:Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrosis, the final common pathway leading to cirrhosis and liver failure for nearly every cause of chronic liver disease. Activation of HSCs in response to injury represents the key step in hepatic fibrogenesis, and is characterized by a phenotypic change from a non-fibrogenic, quiescent HSC to a fibrogenic HSC myofibroblast that secretes extracellular matrix proteins responsible for the fibrotic scar. We developed a small molecule screen to identify compounds that revert fibrotic human HSC myofibroblasts to an inactive phenotype through the quantification of lipid droplets with fluorescent microscopy. Conditions were optimized in a 384-well format using culture in Matrigel as a positive control. We screened 1600 compounds and identified 30 small molecules that induce reversion to an inactive phenotype. Among the hits, we identified five tricyclic antidepressants (TCAs) and showed that this class of drugs also repressed ACTA2 and COL1A1 while promoting PPAR-gamma expression. RNA sequencing analysis implicated extracellular matrix proteins and the sphingolipid pathway as a target of the TCAs.
2017-03-02 | GSE78853 | GEO