Single-cell transcriptional profiling of human cholestatic livers
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA996053 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25321906_1.fastq.gz | Fastqsanger.gz | |||
| SRR25321906_2.fastq.gz | Fastqsanger.gz | |||
| SRR25321907_1.fastq.gz | Fastqsanger.gz | |||
| SRR25321907_2.fastq.gz | Fastqsanger.gz | |||
| SRR25321908_1.fastq.gz | Fastqsanger.gz |
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Project description:Cholestatic liver diseases are characterized by excessive accumulation of bile acids in the liver. The involvement of local tissue microenvironment in cholestatic diseases remains poorly understood. Here, we performed a comprehensive analysis of liver single-cell transcriptomic study of human cholestatic liver diseases. Our study involved 9 liver samples obtained from 7 patients diagnosed with hepatatrophia resulting from cholestasis. By utilizing single-cell data, we gained valuable insights into the specific functions of endothelial cells (EC) in response to chenodeoxycholic acid during cholestasis. The findings from our study hold the potential to lay the groundwork for personalized therapeutic approaches in the future, tailored to the individual needs of patients.
2023-07-22 | GSE237622 | GEO
Project description:Transcriptional Profiling of Pediatric Cholestatic Livers Identifies Three Distinct Macrophage Populations
| PRJNA686999 | ENA
Project description:We characterize three subpopulations of cholestatic macrophages in pediatric patients with biliary atresia (BA) and Alagille syndrome (ALGS).
2020-12-22 | GSE163650 | GEO
Project description:Cholestasis is a multifactorial disorder that compromises liver function. We wanted to examine Phase I and II drug metabolism in cholestatic livers. We performed high-throughput sequencing on livers from Fxr-/- Shp-/- double knockout mice, which mimic juvenile cholestasis. Next, we used comparative transcriptomic approach to test if the induction in drug metabolism is also seen in models of liver injury, including steatosis, regeneration and bile acid-stressed livers.
2020-06-01 | GSE116627 | GEO
Project description:Background & aimsLimited understanding of the role for specific macrophage subsets in the pathogenesis of cholestatic liver injury is a barrier to advancing medical therapy. Macrophages have previously been implicated in both the mal-adaptive and protective responses in obstructive cholestasis. Recently two macrophage subsets were identified in non-diseased human liver; however, no studies to date fully define the heterogeneous macrophage subsets during the pathogenesis of cholestasis. Here, we aim to further characterize the transcriptional profile of macrophages in pediatric cholestatic liver disease.MethodsWe isolated live hepatic immune cells from patients with biliary atresia (BA), Alagille syndrome (ALGS), and non-cholestatic pediatric liver by fluorescence activated cell sorting. Through single-cell RNA sequencing analysis and immunofluorescence, we characterized cholestatic macrophages. We next compared the transcriptional profile of pediatric cholestatic and non-cholestatic macrophage populations to previously published data on normal adult hepatic macrophages.ResultsWe identified 3 distinct macrophage populations across cholestatic liver samples and annotated them as lipid-associated macrophages, monocyte-like macrophages, and adaptive macrophages based on their transcriptional profile. Immunofluorescence of liver tissue using markers for each subset confirmed their presence across BA (n = 6) and ALGS (n = 6) patients. Cholestatic macrophages demonstrated reduced expression of immune regulatory genes as compared to normal hepatic macrophages and were distinct from macrophage populations defined in either healthy adult or pediatric non-cholestatic liver.ConclusionsWe are the first to perform single-cell RNA sequencing on human pediatric cholestatic liver and identified three macrophage subsets with distinct transcriptional signatures from healthy liver macrophages. Further analyses will identify similarities and differences in these macrophage sub-populations across etiologies of cholestatic liver disease. Taken together, these findings may allow for future development of targeted therapeutic strategies to reprogram macrophages to an immune regulatory phenotype and reduce cholestatic liver injury.
| S-EPMC7790256 | biostudies-literature
Project description:High-throughput sequencing reveals induction of drug metabolism in various cholestatic livers
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Project description:We used microarrays to provide a transcriptomic signature of different types of cholestasis evoked by 3 different drugs and obstructive surgery Adverse outcome pathways (AOPs) have been recently introduced as tools to map the mechanisms underlying toxic events relevant for chemical risk assessment. AOPs particularly depict the linkage between a molecular initiating event and an adverse outcome through a number of intermediate key events. An AOP has been previously introduced for cholestatic liver injury. The objective of this study was to test the robustness of this AOP for different types of cholestatic insult and the in vitro to in vivo extrapolation. For this purpose, in vitro samples from human hepatoma HepaRG cell cultures were exposed to cholestatic drugs (i.e. intrahepatic cholestasis), while in vivo samples were obtained from livers of cholestatic mice (i.e. extrahepatic cholestasis). The occurrence of cholestasis in vitro was confirmed through analysis of bile transporter functionality and bile acid analysis. Transcriptomic analysis revealed inflammation and oxidative stress as key events in both types of cholestatic liver injury. Major transcriptional differences between intrahepatic and extrahepatic cholestatic liver insults were observed at the level of cell death and metabolism. Novel key events identified by pathway analysis included endoplasmic reticulum stress in intrahepatic cholestasis, and autophagy and necroptosis in both intrahepatic as extrahepatic cholestasis. This study demonstrates that AOPs constitute dynamic tools that should be frequently updated with new input information.
2020-06-16 | GSE152494 | GEO
Project description:To study molecular differences betweeem wild-type and cholestatic livers of a Jag1Ndr mouse model of Alagille syndrome (Andersson, Chivukula, Hankeova, et al. Gastroenterology, 2018;154(4):1080-1095), we used single cell RNA sequencing (scRNA-seq) of prenatal (E16.5) and early postnatal (P3) livers.
2023-07-14 | GSE236483 | GEO
Project description:Bile acid accumulation and subsequent liver damage is a frequent adverse effect induced by drugs. Considerable efforts have therefore been focused on the introduction and characterization of tools that allow reliable prediction of this type of drug-induced liver injury. Among those are the cholestatic index and transcriptomic profiling, which are typically assessed in in vitro settings. The present study was set up to test the applicability of both tools to non-pharmaceutical compounds with cholestatic potential, including the industrial compound bis(2-ethylhexyl)phthalate, the cosmetic ingredients triclosan and octynoic acid, the herbicides paraquat and quizalofop-para-ethyl, and the food additives sunset yellow and tartrazine, in a human hepatoma cell culture model of cholestatic liver injury. The cholestatic index method showed cholestatic liability of sunset yellow, tartrazine and triclosan. Of those, tartrazine induced transcriptional changes reminiscent of the transcriptional profile of cholestatic drugs. Furthermore, a number of genes were found to be uniquely modulated by tartrazine, in accordance with the cholestatic drugs atazanavir, cyclosporin A and nefazodone, which may have potential as novel transcriptomic biomarkers of chemical-induced cholestatic liver injury. In conclusion, unambiguous identification of the non-pharmaceutical compounds tested in this study as inducers of cholestasis could not be achieved.
2021-03-18 | GSE169072 | 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