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Multicellular liver organoid model for recapitulating hepatitis C virus infection and non-alcoholic fatty liver disease progression [scRNA-Seq]

ABSTRACT: Hepatitis C virus (HCV) infection has been successfully managed by anti-viral therapies, however, high prevalence to severe chronic liver disease state including non-alcoholic fatty liver disease (NAFLD) is a problem encountered even after the cure of hepatitis C. Moreover, there is currently no reliable in vitro model capable of investigating host-viral interactions and monitoring the progression of viral hepatitis to chronic liver diseases. Recent organoid technology has been reported for successful infection of HCV, but there is still lack of non-parenchymal cells, which play a crucial role in disease progression. Here, we provided a novel multicellular liver organoid model using co-culture system of macrophages and liver organoids differentiated from the same cell source, human embryonic stem cells. Surprisingly, HCV infection led potent lipid accumulation in liver organoids through regulation of host lipid metabolism, which was further promoted by macrophage co-culture. Lipid enriched condition provided by longterm-treatment with fatty acid accelerated potent HCV amplification and further promotion of inflammation and fibrosis progression. Therefore, our model may be a valuable novel platform recapitulating diverse phenotypes with host-virus intercommunication and inter-cellular interactions and further progressive features of hepatitis C-associated chronic NAFLD progression of patients with HCV.

ORGANISM(S): Homo sapiens

PROVIDER: GSE229608 | GEO | 2024/05/05

REPOSITORIES: GEO

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Multicellular liver organoid model for recapitulating hepatitis C virus infection and non-alcoholic fatty liver disease progression [RNA-Seq]

Project description:Hepatitis C virus (HCV) infection has been successfully managed by anti-viral therapies, however, high prevalence to severe chronic liver disease state including non-alcoholic fatty liver disease (NAFLD) is a problem encountered even after the cure of hepatitis C. Moreover, there is currently no reliable in vitro model capable of investigating host-viral interactions and monitoring the progression of viral hepatitis to chronic liver diseases. Recent organoid technology has been reported for successful infection of HCV, but there is still lack of non-parenchymal cells, which play a crucial role in disease progression. Here, we provided a novel multicellular liver organoid model using co-culture system of macrophages and liver organoids differentiated from the same cell source, human embryonic stem cells. Surprisingly, HCV infection led potent lipid accumulation in liver organoids through regulation of host lipid metabolism, which was further promoted by macrophage co-culture. Lipid enriched condition provided by longterm-treatment with fatty acid accelerated potent HCV amplification and further promotion of inflammation and fibrosis progression. Therefore, our model may be a valuable novel platform recapitulating diverse phenotypes with host-virus intercommunication and inter-cellular interactions and further progressive features of hepatitis C-associated chronic NAFLD progression of patients with HCV.

2024-05-05 | GSE229596 | GEO

A temporal proteogenomic atlas of HCV-host interactions unravels cell circuits driving viral and metabolic liver disease.

Project description:Background and aims: Hepatitis C virus (HCV) infection is a major cause of liver disease including steatosis, fibrosis and liver cancer. Viral cure cannot fully eliminate the risk of disease progression and hepatocellular carcinoma (HCC) in advanced liver disease. The mechanisms for establishment of infection, liver disease progression and hepatocarcinogenesis are only partially understood. To address these questions, we probed the functional proteogenomic architecture of HCV infection within a hepatocyte-model. Methods: Time-resolved HCV infection of hepatocyte-like cells was analyzed by RNA sequencing, proteomics, metabolomics, and leveraged by integrative genomic analyses. Using differential expression, gene set enrichment analyses, and protein-protein interaction mapping we identified pathways relevant for liver disease pathogenesis that we validated in livers of 216 cirrhotic patients with HCV. Results: We uncovered marked changes in the protein expression of gene sets involved in innate immunity, metabolism and hepatocarcinogenesis. In infected cells, HCV enhances glucose metabolism and creates a Warburg-like shift of the lactate flux. HCV infection impaired the formation of peroxisomes -organelles required for long-chain fatty acid oxidation- causing intracellular fatty acid accumulation, which is a hallmark of non-alcoholic fatty liver disease (NAFLD). Ex vivo studies confirmed perturbed peroxisomes and revealed an association of hepatic catalase expression with clinical outcomes and phenotypes in HCV-associated cirrhosis, NAFLD and HCC cohorts. Conclusion: Our integrative analyses uncover how HCV perturbs the hepatocyte cell circuits to drive chronic liver disease and hepatocarcinogenesis. This proteogenomic atlas of HCV infection provides a model for the discovery of novel drivers for viral- and non-viral induced liver disease.

2019-04-17 | GSE126831 | GEO

Transcription profiling of human liver biopsies from HCV associated advance disease state patients

Project description:Introduction: Mechanisms that contribute to the pathogenesis of liver damage caused by hepatitis C virus (HCV) are not fully understood. Our previous work on liver biopsies from chronic HCV patients has shown modulation of the expression of certain cell cycle proteins indicating HCV-induced modifications of cell cycle events. We therefore hypothesize that HCV infection disrupts normal regulation of cell cycle that contributes to disease progression. Objective: To identify molecular disruptions during the course of HCV-associated disease progression, using liver biopsy specimens of chronic hepatitis C patients. Methods: Liver biopsy samples classified on histological basis as early (fibrosis stage 0-1) or advanced (fibrosis stage 3-4) disease stage were studied using oligonucleotide array ( HG U133 Plus 2.0, Affymetrix GeneChipâ¢ System). For comparison, liver specimens from patients with non-viral hepatitis were also analyzed by microarray. Expression data was analyzed using Genespring (GX 7.2) and Ingenuity Pathway analysis (3.0). The differential expression of selected cell cycle genes (cyclin D2, KPNA2, HERC5 and Bcl-2) identified after microarray analysis was confirmed by quantitative real-time RT-PCR. Results: Microarray analysis revealed two-fold or greater transcriptional change in 792 genes of the total 38,500 known human genes in HCV-advance disease stage (HCV-A) as compared to HCV-early disease stage (HCV-E). Most of the genes have a defined role in immune response, extracellular matrix and cell cycle and apoptosis. Experiment Overall Design: Liver biopsy samples were collected from patients of (a) HCV-infected early disease stage (HCV-E, control 1) (b) non-HCV advance disease stage (control 2) and (c) HCV-infected advance disease stage (HCV-A) for RNA extraction. Equal amount of RNA was pooled from samples (n=4)within each group and hybridized to HG-U133 Plus 2.0 array.

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The Effect of Hepatitis C Virus Infection on Host Gene Expression

Project description:Hepatitis C Virus is a leading cause of chronic liver disease. The identification and characterisation of key host cellular factors that play a role in the HCV replication cycle is important for the understanding of disease pathogenesis and the identification of novel anti-viral therapeutic targets. Gene expression profiling of HCV infected Huh7 cells by microarray analysis was performed to identify host cellular genes that are transcriptionally regulated by infection. The expression of host genes involved in cellular defence mechanisms (apoptosis, proliferation and anti-oxidant responses), cellular metabolism (lipid and protein metabolism) and intracellular transport (vesicle trafficking and cytoskeleton regulation) was significantly altered by HCV infection. The gene expression patterns identified provide insight into the potential mechanisms that contribute to HCV associated pathogenesis. These include an increase in pro-inflammatory and pro-apoptotic signalling and a decrease in the anti-oxidant response pathways of the infected cell.

2010-05-01 | GSE20948 | GEO

Expression data of HCV-associated advance disease state

Project description:Introduction: Mechanisms that contribute to the pathogenesis of liver damage caused by hepatitis C virus (HCV) are not fully understood. Our previous work on liver biopsies from chronic HCV patients has shown modulation of the expression of certain cell cycle proteins indicating HCV-induced modifications of cell cycle events. We therefore hypothesize that HCV infection disrupts normal regulation of cell cycle that contributes to disease progression. Objective: To identify molecular disruptions during the course of HCV-associated disease progression, using liver biopsy specimens of chronic hepatitis C patients. Methods: Liver biopsy samples classified on histological basis as early (fibrosis stage 0-1) or advanced (fibrosis stage 3-4) disease stage were studied using oligonucleotide array ( HG U133 Plus 2.0, Affymetrix GeneChip™ System). For comparison, liver specimens from patients with non-viral hepatitis were also analyzed by microarray. Expression data was analyzed using Genespring (GX 7.2) and Ingenuity Pathway analysis (3.0). The differential expression of selected cell cycle genes (cyclin D2, KPNA2, HERC5 and Bcl-2) identified after microarray analysis was confirmed by quantitative real-time RT-PCR. Results: Microarray analysis revealed two-fold or greater transcriptional change in 792 genes of the total 38,500 known human genes in HCV-advance disease stage (HCV-A) as compared to HCV-early disease stage (HCV-E). Most of the genes have a defined role in immune response, extracellular matrix and cell cycle and apoptosis. Keywords: HCV-advance disease state

2007-11-01 | GSE7741 | GEO

Small tRNA-derived RNAs are increased and more abundant than microRNAs in chronic hepatitis B and C

Project description:Small, non-coding RNAs control gene expression post-transcriptionally and play important roles in virus-host interactions. Within the liver, the microRNA (miRNA) miR-122 is essential for replication of hepatitis C virus (HCV), while repression of miR-148a by hepatitis B virus (HBV) may enhance tumorigenesis. Despite their importance to the outcome of these infections, few previous studies have described unbiased profiling of small RNAs in the liver during chronic viral hepatitis. Here, we sequenced small (14-40 nts) RNAs in liver from subjects with chronic hepatitis B and C. We found that small RNAs derived from tRNAs, specifically 5’ tRNA-halves (“5’ tRHs”, ~31-34 nts), are abundant in liver and significantly increased during chronic viral infection in humans and also chimpanzees. In most infected livers, 5’ tRH abundance exceeded that of miRNAs. In contrast, in hepatocellular carcinoma (HCC) tissue from these subjects, tRH abundance was reduced concomitant with decreased expression of the tRNA-cleaving ribonuclease, angiogenin. Although tRHs have been identified in mice, our results show they are abundantly expressed in human tissue, increased in chronic viral infection, and decreased in liver cancer. Our findings highlight the potential biological and clinical relevance of these small non-coding RNAs. Small RNA-seq of liver samples from control subjects (n=4), subjects with chronic hepatitis B (n=4) and hepatitis B associated hepatocellular carcinoma (n=4, 3 out of 4 matched with non-tumor tissue) and subjects with chronic hepatitis C (n=4) and tissue from hepatocellular carcinoma of the same patients. Also, small RNA-seq of AGO2 and IgG pulldown in FT3-7 cells. Sequenced AGO2 pulldown (n=3), IgG pulldown (n=2) and total small RNA from FT3-7 cells (n=3). This dataset is part of the TransQST collection.

2014-12-18 | E-GEOD-57381 | biostudies-arrayexpress

Exon analysis of HCV tumor promoting effect

Project description:The hepatitis C virus (HCV) is one of the major risk factors for the development of hepatocellular carcinoma (HCC). Nevertheless, transgenic mice which express the whole HCV polyprotein (HCV-Tg) do not develop HCC. Whereas chronic HCV infection causes inflammation in patients, in HCV-Tg mice, the host immune reaction against viral proteins is lacking. We aimed to test the role of HCV proteins in HCC development on the background of chronic inflammation in vivo. We crossed the HCV-Tg mice which do not produce HCC with the Mdr2-knockout (Mdr2-KO) mice which develop inflammation-associated HCC, to generate Mdr2-KO/HCV-Tg mice. We studied the effect of the HCV transgene on tumor incidence, hepatocyte mitosis and apoptosis, and on gene expression in the liver of produced mice.

2009-03-22 | GSE12184 | GEO

Transcript analysis of HCV tumor promoting effect

2009-03-22 | GSE12183 | GEO

HCV tumor promoting effect is dependent on host genetic background

2009-03-22 | GSE12185 | GEO

miR-122-dependent binding of TNRC6 to HCV RNA

Project description:The liver-specific microRNA, miR-122, is an essential host factor for replication of hepatitis C virus (HCV), an important infectious cause of chronic liver disease and hepatocellular carcinoma. miR-122 stabilizes the positive-strand HCV RNA genome and promotes viral RNA synthesis by binding two closely spaced sites (S1 and S2) near the 5’ end of the genome in association with Ago2. Ago2 is essential for both host factor activities, but whether other host proteins are involved is unknown. Using a quantitative proteomics approach, we identified TNRC6A (GW182) and its paralogs (TNRC6B and TNRC6C), as functionally important components of the miR-122/Ago2 host factor complex binding HCV RNA. Depletion of any two TNRC6 proteins reduced HCV replication in Huh-7.5 cells,but did not reduce viral RNA stability or translational activity, but rather dampened miR-122 stimulation of viral RNA synthesis. However, TNRC6 depletion had no effect on replication of HCV in which S2 was mutated so that miR-122 binds only S1, whereas it significantly enhanced replication when S1 was mutated and only S2 bound by miR-122. Consistent with this, we found that TNRC6 proteins preferentially associate with the S1 site, and that the association of Ago2 with S2 is increased in TNRC6-depleted cells. Collectively, these data suggest a model in which TNRC6 proteins, which are known to interact with Ago2, preferentially direct the miR-122/Ago2 complex to S1 while restricting its association with S2, thereby fine tuning the spatial organization of miR-122/Ago2 complexes bound to the viral RNA.

2019-04-24 | PXD013054 | Pride

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