RNA-seq of human hepatic arteries in a study of primary sclerosing cholangitis
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ABSTRACT:
PROVIDER: PRJEB54582 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR9922200_1.fastq.gz | Fastqsanger.gz | |||
| ERR9922200_2.fastq.gz | Fastqsanger.gz | |||
| ERR9922201_1.fastq.gz | Fastqsanger.gz | |||
| ERR9922201_2.fastq.gz | Fastqsanger.gz | |||
| ERR9922202_1.fastq.gz | Fastqsanger.gz |
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Project description:PSC is a chronic inflammatory condition of the biliary tree causing biliary strictures and fibrosis and predisposes to cholangiocarcinoma. Traditionally it is considered a primary disorder of the bile duct epithelia. Here we investigate whether injury to the arterial blood supply may contribute to PSC. Hepatic arteries were collected from 8 patients at the time of liver transplantation: 4 with PSC and 4 disease controls. Samples were used for RNA-sequencing, differential expression and pathways analyses.
2023-07-01 | E-MTAB-11917 | biostudies-arrayexpress
Project description:Background. Abcb4 (-/-) mice secrete phosphatidylcholine-deficient bile and develop sclerosing cholangitis (SC). The cholangitis involves differential hepatic transcription of genes whose products govern inflammation, activation of hepatic stellate cells and fibrosis. This study was undertaken to test the hypothesis that several genes involved in regulation of tissue inflammation and fibrosis display transcription rates that reflect SC disease activity. Methods. Abcb4 (-/-) mice fed cholic acid (CA) display high SC activity and ursodeoxycholic acid (UDCA) fed mice display low SC activity. Differential hepatic transcription of genes was accordingly measured in abcb4 (-/-) mice maintained on CA- and UDCA-supplemented diets using cDNA microarrays. Abcb4 (+/+) mice served as controls. The differential transcription of selected genes was verified by real time polymerase chain reaction. Liver tissue pathology was quantified by histopathology scoring and immunohistochemistry to visualize bile duct cells and activated hepatic stellate cells. Results. Differential transcription of Ccl2, Ccl20, Cxcl10, Nfκb1, Nfκb2, Tgfβ1, Tgfβ2, Sparc, Ctgf, Lgals3, Elf3, Spp1, Pdgfa, Pdgfrb, Col1a1, Col1a2 and Col4a1 genes paralleled the differing SC activities of cholic acid- and UDCA-fed abcb4 (-/-) mice. Histopathology scores and immunohistochemistry showed greatly enhanced activation of hepatic stellate cells during high SC activity due to CA feeding. Conclusion. Differential transcription of several genes relating to tissue inflammation and hepatic stellate cell activation parallels SC activity in abcb4 (-/-) mice. Data on their differential transcription may be used to gauge SC disease activity.
2008-08-20 | GSE11507 | GEO
Project description:CCL24 is a profibrotic, proinflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Mdr2-/- mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24 neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under profibrotic conditions in primary human cholangiocytes and macrophages and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of PSC patients. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in PSC patients via reduced liver inflammation, fibrosis and cholestasis.
2023-04-30 | GSE228596 | GEO
Project description:CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis
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Project description:Il-17 Signaling in Primary Sclerosing Cholangitis Patient-Derived Organoids
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Project description:Associations of fecal bile acids, diet, and intestinal microbes with markers of disease progression in primary sclerosing cholangitis disease
| PRJEB60105 | ENA
Project description:Background and aims: Signal transducer and activator of transcription 3 (Stat3) is the main mediator of interleukin-6 type cytokine signaling required for hepatocyte proliferation and hepatoprotection but its role in sclerosing cholangitis and other cholestatic liver diseases remains unresolved. Methods: We investigated the role of Stat3 in inflammation-induced cholestatic liver injury and used mice lacking the multidrug resistance gene 2 (mdr2-/-) as a model for SC. Results: We demonstrate that conditional inactivation of stat3 in hepatocytes and cholangiocytes (stat3 delta hc) of mdr2-/- mice strongly aggravated bile acid-induced liver injury and fibrosis. A similar phenotype was observed in mdr2-/- mice lacking IL-6 production. Biochemical and molecular characterization suggested that Stat3 exerts hepatoprotective functions in both, hepatocytes and cholangiocytes. Loss of Stat3 in cholangiocytes led to increased expression of TNFα which might reduce the barrier function of bile ducts. Loss of Stat3 in hepatocytes led to upregulation of bile acid biosynthesis genes and downregulation of hepatoprotective epidermal growth factor receptor and insulin-like growth factor 1 signaling pathways. Consistently, stat3deltahc mice were more sensitive to cholic acid-induced liver damage than control mice. Conclusions: Our data suggest that Stat3 prevents cholestasis and liver damage in sclerosing cholangitis via regulation of pivotal functions in hepatocytes and cholangiocytes. Affymetrix microarray analyses was performed to identify metabolic and molecular pathways in stat3Dhc mdr2-/- mice that lead to cholestasis and bile acid-induced liver injury. To avoid false positive results that are due to differential cellular composition, we defined the onset of fibrosis and expression of fibrogenic factors in stat3Dhc mdr2-/- mice.
2010-10-20 | E-GEOD-18759 | biostudies-arrayexpress
Project description:Primary sclerosing cholangitis (PSC) is characterized by chronic inflammation and progressive fibrosis of the biliary tree. The bile acid receptor TGR5 is found on biliary epithelial cells (BECs), where it promotes secretion, proliferation and tight junction integrity. Thus, we speculated that changes in TGR5 expression in BECs may contribute to PSC pathogenesis.
2021-03-12 | GSE168758 | GEO
Project description:The pathogenesis of primary sclerosing cholangitis (PSC) is unclear, although studies implicate IL-17A as an inflammatory mediator in this disease. However, a direct assessment of IL-17 signaling in PSC cholangiocytes is lacking. Cholangiocytes obtained from PSC and non-PSC patients by endoscopic retrograde cholangiography (ERC) were cultured as extrahepatic cholangiocyte organoids (ECO). The ECO were treated with vehicle or IL-17A and assessed by NanoString analysis, single cell RNA sequencing (scRNA-seq), and whole genome sequencing (WGS). The secretome was assessed by Olink analysis. Unsupervised clustering of all integrated scRNA-seq data identified 8 cholangiocyte clusters which did not differ between non-PSC and PSC ECO. However, PSC ECO cells demonstrated a much more robust response to IL-17 treatment, noted by an increased number of differentially expressed genes (DEG) after the treatment with IL-17A, compared to non-PSC ECO. After rigorous filtering, WGS identified the presence of somatic mutations that were shared between PSC ECO. However, no somatic mutations dysregulating genes in the IL-17 pathway were identified. The secretome of PSC ECO contained more abundant chemokines and cytokines under basal conditions and following IL-17A stimulation when compared to non-PSC ECO. In conclusion, PSC and non-PSC patient derived ECO respond differently to IL-17 stimulation regardless of mutational status, suggesting a change in epigenetic regulation and the implication of this pathway in the pathogenesis of PSC.
2024-01-29 | GSE239283 | GEO
Project description:Intestinal expression of ASBT determines the sclerosing cholangitis phenotype.
| PRJNA546456 | ENA