RNA-seq analysis of endothelial-specific Myc overexpression mice after bile duct liagtion surgery
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE237384 | GEO | 2023/07/18
REPOSITORIES: GEO
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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: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: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:Background & Aims: Macrophages (MF) play a role in neonatal etiologies of obstructive cholestasis, however, the role for precise MF subsets remains poorly defined. We developed a neonatal murine model of bile duct ligation (BDL) to characterize etiology-specific differences in neonatal cholestatic MF polarization. Approach & Results: Neonatal BDL surgery was performed on female BALB/c mice at 10 days of life (DOL) with sham laparotomy as controls. Comparison was made to the Rhesus Rotavirus (RRV)-induced murine model of biliary atresia (BA). Evaluation of changes at day 7 after surgery (BDL and sham groups) and murine BA (DOL14) included laboratory data, histology (H&E, anti-CD45 and anti-CK19 staining), flow cytometry of MF subsets by MHCII and Ly6c expression, and single cell RNA-sequencing (scRNA-seq) analysis. Neonatal BDL achieved a 90% survival rate; mice had elevated bile acids, bilirubin, and alanine aminotransferase (ALT) versus controls (p < 0.05 for all). Histology demonstrated hepatocellular injury, CD45+ portal infiltrate, and CK19+ bile duct proliferation in neonatal BDL. Comparison to murine BA showed increased ALT in neonatal BDL despite no difference in histology Ishak score. Neonatal BDL had significantly lower MHCII-Ly6c+ MF versus murine BA, however, scRNA-seq identified greater etiology-specific MF heterogeneity with increased endocytosis in neonatal BDL MF versus cellular killing in murine BA MF. Conclusions: We generated an innovative murine model of neonatal obstructive cholestasis with low mortality. This model enabled comparison to murine BA to define etiology-specific cholestatic MF function. Further comparisons to human data may enable development of immune modulatory therapies to improve patient outcomes.
2023-09-06 | GSE228996 | GEO
Project description:We performed gene expression profile of the liver at 7 days after the BDL procedure.
2010-04-01 | E-MEXP-2583 | biostudies-arrayexpress
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
Project description:Infants with neonatal cholestasis are prone to neurodevelopmental deficits including neuromotor function. Accumulation of potentially neurotoxic molecules in the bloodstream including ammonia and bile acids and malabsorption of lipids may affect neurodevelopment in these patients. This study examined neuromotor function and bile acid and lipid composition of the brain in a piglet model of obstructive neonatal cholestasis via bile duct ligation (BDL) surgery. Results showed that BDL piglets had compromised balance and increased liver enzyme levels, liver fibrosis and bile duct proliferation compared to SHAM piglets. Plasma and cerebellum bile acid profiles differed between BDL and SHAM piglets with hyocholic acid and conjugated bile acid forms dominating in the BDL group. In the cerebellum there were different lipid profiles, but similar gene expression profiles between the two groups.
2022-06-01 | GSE180600 | GEO
Project description:Cholelithiasis-induced cholestasis is one of the most common causes of hospitalization due to gastrointestinal disease, yet considerable knowledge gaps exist in the pathogenesis of this disease. This can partially be explained by inadequate characterization of experimental cholestasis models. Therefore, we compared the transcriptional profile of commonly used mouse models for obstructive cholestasis and benchmarked them to human disease to identify the model(s) best suited for cholelithiasis-induced cholestasis research and to uncover conserved mechanisms involved in human and murine cholestasis. Selected mouse models included bile duct ligation (BDL) surgery, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet, associated with extra- and intrahepatic obstructive cholestasis, respectively, and a drug-induced cholestasis model relying on cyclosporin A (CsA), in an acute and chronic setting. Human samples were collected from patients with cholelithiasis-induced cholestasis of an acute and recurrent nature. RNA sequencing was performed on mouse and human liver tissue. Both the BDL and DDC models, but not the CsA model, were shown to be applicable for studying cholelithiasis-induced cholestasis, with transcriptomic profiles that highly correspond to acute cholestasis in human patients. In particular, the conservation of canonical pathways related to the inflammatory response and cytoskeleton organization, in which the Rho family GTPase is involved, were identified. This study furthermore revealed some promising mechanistic-based transcriptomic biomarkers relevant for murine and human cholestasis, which could potentially be useful for robust prediction and detection of diverse types of cholestatic liver disease.
2023-05-02 | GSE183882 | GEO
Project description:Cholelithiasis-induced cholestasis is one of the most common causes of hospitalization due to gastrointestinal disease, yet considerable knowledge gaps exist in the pathogenesis of this disease. This can partially be explained by inadequate characterization of experimental cholestasis models. Therefore, we compared the transcriptional profile of commonly used mouse models for obstructive cholestasis and benchmarked them to human disease to identify the model(s) best suited for cholelithiasis-induced cholestasis research and to uncover conserved mechanisms involved in human and murine cholestasis. Selected mouse models included bile duct ligation (BDL) surgery, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet, associated with extra- and intrahepatic obstructive cholestasis, respectively, and a drug-induced cholestasis model relying on cyclosporin A (CsA), in an acute and chronic setting. Human samples were collected from patients with cholelithiasis-induced cholestasis of an acute and recurrent nature. RNA sequencing was performed on mouse and human liver tissue. Both the BDL and DDC models, but not the CsA model, were shown to be applicable for studying cholelithiasis-induced cholestasis, with transcriptomic profiles that highly correspond to acute cholestasis in human patients. In particular, the conservation of canonical pathways related to the inflammatory response and cytoskeleton organization, in which the Rho family GTPase is involved, were identified. This study furthermore revealed some promising mechanistic-based transcriptomic biomarkers relevant for murine and human cholestasis, which could potentially be useful for robust prediction and detection of diverse types of cholestatic liver disease.
2023-05-02 | GSE183754 | GEO