Circulating extracellular vesicles with liver-specific RNA species are potential biomarkers for early cholestasis-induced liver fibrosis [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA701905 | ENA |
REPOSITORIES: ENA
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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: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:Circulating extracellular vesicles with liver-specific RNA species are potential biomarkers for early cholestasis-induced liver fibrosis.
| PRJNA701900 | ENA
Project description:Circulating extracellular vesicles with liver-specific RNA species are potential biomarkers for early cholestasis-induced liver fibrosis [mRNA-seq]
| PRJNA701906 | ENA
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
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-02-28 | GSE166754 | GEO
Project description:Cholestasis, a serious complication of liver metastasis (LM), contributes to dismal prognosis in patients with colorectal cancer and LM. However, the mechanism underlying the effect of cholestasis on the development of LM or pre-metastatic microenvironment in the liver remains elusive. In this study, we discovered that cholestasis accelerated the progression of LM and is associated with increased neutrophil infiltration, T-cell exclusion, and exhaustion. Besides, Tβ-MCA and GCA promoted the expression of Arg1 and iNOS in neutrophils via the p38/MAPK signaling pathway. The significant suppression of the activation and cytotoxic effects of CD8+ T cells during co-culture with BA-pretreated neutrophils indicated that BAs directly induce the polarization of immunosuppressive neutrophils. Importantly, targeting BA anabolism with Obeticholic acid effectively suppressed the LM of colorectal cancer in a cholestasis mouse model. Our findings suggest that cholestasis, associated with the failure to achieve drainage of primary BAs, accelerates the progression of LM by remodeling the tumor immune microenvironment. Moreover, targeting BA anabolism with OCA may represent a therapeutic strategy for cholestasis-associated LM of colorectal cancer.
2024-07-10 | GSE209836 | GEO
Project description:Increasing studies suggested the treatment potential of mesenchymal stem cells in variety diseases. Evidence showed that MSCs could promote injured tissue repair and improve disease mortality. These indicated that MSC transplantation may be an ideal candidate for cholestasis treatment.We found that MenSC transplantation could significantly improve the symptoms and pathological changes of DDC-induced cholestasis liver injury in mice.
2022-02-16 | PXD028425 | Pride
Project description:Cholestasis is characterized by disrupted bile flow from the liver to the small intestine. Although etiologically different cholestasis display similar symptoms, diverse factors can contribute to the progression of the disease and determines the appropriate therapeutic option. Therefore, stratifying cholestatic patients is essential for the development of tailor-made treatment strategies. Here, we have analyzed the liver proteome from cholestatic patients of different etiology. 7,161 proteins were identified and quantified, of which 263 were differentially expressed between control and cholestasis groups. These differential proteins point to deregulated cellular processes that explain part of the molecular framework of cholestasis progression. However, the clustering of different cholestasis types was limited. Therefore, a machine learning pipeline was designed to identify a panel of 20 differential proteins that segregate different cholestasis groups with high accuracy and sensitivity. In summary, proteomics combined with machine learning algorithms provides valuable insights into the molecular mechanisms of cholestasis progression and a panel of proteins to discriminate across different types of cholestasis. This strategy may prove useful to develop precision medicine approaches for patient care.
2024-05-22 | PXD047823 | Pride