Transcriptomic analysis of liver lymphatic endothelial cell (LyEC) isolated from sham or bile duct ligation (BDL)-induced cholestasis mouse model
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE276093 | GEO | 2024/12/31
REPOSITORIES: GEO
Similar Datasets
Project description:The aim is to characterize rat liver fibrosis induced by bile duct ligation (BDL). To induce hepatic fibrosis, Male Sprague Dawley rats (9-12 weeks of age and 380-420 g of weight upon arrival, supplied by Beijing Vital River laboratory animal Co., Ltd.) underwent surgery of bile duct ligation (BDL). The bile ducts of Sprague-Dawley rats were ligated after 12 hours of fasting and water deprivation. Rat liver samples were collected from three groups of rats at week 1, 2 and 5 after BDL surgery. Three control groups of rats underwent sham operation, including bile duct mobilization, but without BDL. Three biological replicates were used for each group.
2021-09-29 | E-MTAB-10546 | biostudies-arrayexpress
Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases. Total RNA isolated using TRI Reagent (Sigma, St. Louis, MO) was purified with an RNeasy mini kit (Qiagen, Valencia, CA). Twenty micrograms cRNA was hybridized to a mouse GeneChip (U74Av2, Affymetrix, Santa Clara, CA) at the Siteman Cancer Center GeneChip facility as described by the manufacturer. Analyses used one mouse per chip. Gene expression changes were analyzed using Affymetrix MicroArray Suite 4.0 and GeneChip 3.1 Expression Analysis and Statistical Algorithms (Affymetrix). The complete methodology and full data sets for all 6 analyzed chips are available at http://bioinformatics.wustl.edu.beckerproxy.wustl.edu This study compares the injury and repair processed in wild-type mice after BDL.
2011-06-09 | E-GEOD-29776 | biostudies-arrayexpress
Project description:Cholestatic liver disease (CLD) represents a severe pathological condition that can advance to cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cells (HSCs) is integral to the pathogenesis of CLD. Previous research has indicated that bone marrow mesenchymal stem cells (BMSCs) may offer therapeutic benefits for liver diseases. Nonetheless, the specific therapeutic efficacy and underlying mechanisms of BMSCs in the context of CLD remain inadequately understood. In this study, we aimed to elucidate the therapeutic efficacy and potential therapeutic genes of BMSCs transplantation in a murine model of cholangioligation-induced cholestatic liver fibrosis (CLF).
2024-09-13 | GSE276505 | GEO
Project description:Extrahepatic cholestasis leads to complex injury and repair processes that result in bile infarct formation, neutrophil infiltration, cholangiocyte and hepatocyte proliferation, extracellular matrix remodeling, and fibrosis. To identify early molecular mechanisms of injury and repair after bile duct obstruction, microarray analysis was performed on liver tissue 24 hours after bile duct ligation (BDL) or sham surgery. The most upregulated gene identified encodes plasminogen activator inhibitor 1 (PAI-1, Serpine 1), a protease inhibitor that blocks urokinase plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) activity. Because PAI-1, uPA, and tPA influence growth factor and cytokine processing as well as extracellular matrix remodeling, we evaluated the role of PAI-1 in cholestatic liver injury by comparing the injury and repair processes in wild-type (WT) and PAI-1-deficient (PAI-1-/-) mice after BDL. PAI-1-/- mice had fewer and smaller bile infarcts, less neutrophil infiltration, and higher levels of cholangiocyte and hepatocyte proliferation than WT animals after BDL. Furthermore, PAI-1-/- mice had higher levels of tPA activation and mature hepatocyte growth factor (HGF) after BDL than WT mice, suggesting that PAI-1 effects on HGF activation critically influence cholestatic liver injury. This was further supported by elevated levels of c-Met and Akt phosphorylation in PAI-1-/- mice after BDL. In conclusion, PAI-1 deficiency reduces liver injury after BDL in mice. These data suggest that inhibiting PAI-1 might attenuate liver injury in cholestatic liver diseases.
2011-06-09 | GSE29776 | GEO
Project description:Purpose: Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin-1 (Prom1/CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1-expressing HPCs promote fibrogenesis in cholestatic liver injury. Methods: Using Prom1CreERT2-nLacZ/+;Rosa26Lsl-GFP/+ mice, we traced the fate of Prom1-expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Results: Prom1-expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential towards both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1-expressing HPCs gave rise to both PROM1(+) and PROM1(-) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA-sequencing analysis of GFP(+) Prom1-expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor-b pathway activation. Conclusion: Our data indicate that Prom1-expressing HPCs promote biliary fibrosis by activation of myofibroblasts in cholestatic liver injury.
2020-06-30 | GSE144726 | GEO
Project description:GPCRs are the most productive drug targets and targeted by one third of the drugs in clinical use, however, few GPCRs are reported to participate in liver fibrosis. In this study, we have identified that KCs-enriched GPR65 is upregulated in both human and mouse fibrotic livers and KCs from fibrotic livers. To identify the roles of GPR65 in liver fibrosis, we performed RNA-seq to analyze the effect of Gpr65 deficiency on BDL-induced liver fibrosis. The mice were divided into four groups: sham operation- treated WT mice (n=3), bile duct ligation (BDL)- treated WT mice (n=3), sham operation- treated GPR65-KO mice (n=3) and BDL- treated GPR65-KO mice (n=3).
2023-11-18 | GSE182235 | GEO
Project description:Cirrhosis is a late stage of fibrosis that fatally impairs liver function. Unfortunately, genetic animal models mimicking human cirrhosis are lacking and the molecular mechanisms remain unknown. Here we report the first murine genetic model recapitulating clinical features of cirrhosis, which are induced by hepatocyte-specific elimination of microspherule protein 1 (MCRS1), a member of the non-specific lethal (NSL) and INO80 chromatin modifier complexes. Deregulation of bile acid (BA) transporter expression, revealed by proteomic analysis of MCRS1-depleted mouse livers, with pronounced downregulation of the Na+-taurocholate cotransporting polypeptide (NTCP), causes BA accumulation in liver sinusoids. Genetic ablation of the BA receptor FXR in hepatic stellate cells (HSCs) suppresses bile duct ligation (BDL)-induced fibrosis in mice. Moreover, in vitro experiments demonstrate that fibrotic marker expression is reduced in FXR-depleted HSCs cultured in conditioned medium containing high BAs from MCRS1-depleted hepatocytes. Additionally, hepatocytic MCRS1 overexpression increases their NTCP levels, and consequently protects mice against BDL-induced liver fibrosis. Deletion of a putative SANT domain in MCRS1, also revealed by protein sequence analysis and essential for histone H3 (H3) binding, disrupts H3/HDAC1 complex formation. This evicts MCRS1 and HDAC1 from their H3 anchoring sites and increases histone lysine acetylation of BA transporter genes, independently of the NSL or INO80 complexes. Taken together, our data reveal a previously unrecognized function of MCRS1 as a novel histone acetylation regulator that binds to H3, and recruits a novel chromatin-modifying complex that maintains gene expression homeostasis and liver health. Accordingly, loss of nuclear MCRS1 correlates with increased histone acetylation in human cirrhosis samples. Regulation of histone acetylation might thus be central to cirrhotic development.
2022-05-19 | PXD023026 | Pride
Project description:We report differences in miRNA expression between cholestasis mice and LIX1L knockout cholestasis mice.Liver samples were obtained from mice from different groups, and the liver samples were detected using the Agilent Mouse miRNA Microarray, Release 21.0 (8*60K,Design ID:070155) chip. After the samples were qualitatively controlled, the data were standardized using the Quantile algorithm. According to the analysis confirmation, a total of three groups of differences were compared and the corresponding GO and KEGG were performed.miR-191-3p displayed the most significant reduction in the liver of WT-BDL mice, and the reduced expression of miR-191-3p was restored in Lix1l-/--BDL mice. We demonstrated that miR-191-3p targets and downregulates LRH-1.Finally, we demonstrated that miR-191-3p further alleviated cholestatic liver injury by inhibiting the expression of LRH-1 to inhibit bile acid synthesis.This study provides a reference for the application of a comprehensive miRNA Microarray to characterize differential miRNA expression in cholestasis mice.
2021-01-16 | GSE164903 | GEO
Project description:Aims Biliary diseases represent around 10% of all chronic liver diseases and affect both adults and children. Currently available biochemical tests detect cholestasis but not early liver fibrosis. Circulating extracellular vesicles (EVs) provide a real-time molecular snapshot of the injured organ in a non-invasive way. We thus aimed at searching for a panel of EV-based biomarkers for cholestasis-induced early liver fibrosis using mice models. Results: Progressive and detectable histological evidence of collagen deposition and liver fibrosis was observed as from Day 8 after bile duct ligation (BDL) in mice. Whole transcriptome and small RNA-seq analyses of circulating EVs revealed differentially enriched RNA species after BDL versus sham controls. Unsupervised hierarchical clustering identified a signature that allowed for discrimination between BDL and controls. In particular, 151 microRNAs enriched in BDL-derived EVs were identified, of which 66 were conserved in humans. The liver was an important source of circulating EVs in BDL animals as evidenced by the enrichment of several hepatic mRNAs, such as Albumin, Haptoglobin, Transferrin receptor 1 and Alas2. Interestingly, among experimentally validated miRNAs, miR194-5p and miR29-3p showed similar enrichment patterns also in EVs derived from DDC-treated (drug-induced cholestasis) and MDR2-/- (genetic cholestasis) mice. Innovation A panel of mRNAs and miRNAs contained in circulating EVs, when combined, provides sensitive biomarkers for the early detection of hepatic damage and fibrosis. Conclusion Analysis of EVs for enrichment in miR29-3p and miR194-5p, in combination with hepatic injury RNA markers, could represent a sensitive biomarker panel for the early detection of cholestasis-induced liver fibrosis.
2022-02-28 | GSE166753 | GEO
Project description:Aims Biliary diseases represent around 10% of all chronic liver diseases and affect both adults and children. Currently available biochemical tests detect cholestasis but not early liver fibrosis. Circulating extracellular vesicles (EVs) provide a real-time molecular snapshot of the injured organ in a non-invasive way. We thus aimed at searching for a panel of EV-based biomarkers for cholestasis-induced early liver fibrosis using mice models. Results: Progressive and detectable histological evidence of collagen deposition and liver fibrosis was observed as from Day 8 after bile duct ligation (BDL) in mice. Whole transcriptome and small RNA-seq analyses of circulating EVs revealed differentially enriched RNA species after BDL versus sham controls. Unsupervised hierarchical clustering identified a signature that allowed for discrimination between BDL and controls. In particular, 151 microRNAs enriched in BDL-derived EVs were identified, of which 66 were conserved in humans. The liver was an important source of circulating EVs in BDL animals as evidenced by the enrichment of several hepatic mRNAs, such as Albumin, Haptoglobin, Transferrin receptor 1 and Alas2. Interestingly, among experimentally validated miRNAs, miR194-5p and miR29-3p showed similar enrichment patterns also in EVs derived from DDC-treated (drug-induced cholestasis) and MDR2-/- (genetic cholestasis) mice. Innovation A panel of mRNAs and miRNAs contained in circulating EVs, when combined, provides sensitive biomarkers for the early detection of hepatic damage and fibrosis. Conclusion Analysis of EVs for enrichment in miR29-3p and miR194-5p, in combination with hepatic injury RNA markers, could represent a sensitive biomarker panel for the early detection of cholestasis-induced liver fibrosis.
2022-02-28 | GSE166752 | GEO