Single-cell Transcriptomic Architecture Reveals Dynamic Heterogeneity and Intracellular Crosstalk Features Which Triggers Liver Mallory-Denk Bodies Pathogenesis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201569 | GEO | 2023/06/21
REPOSITORIES: GEO
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Project description:Mallory-Denk bodies (MDBs) are misfolded protein aggregates that include hepatocytes present in liver diseases, and are considered a typical feature of chronic liver diseases. Cholangiocytes are an epithelial cell type constituting the hepatic parenchyma, and play a role in liver regeneration if hepatocyte regeneration is compromised. UbD, which is overexpressed in hepatocellular carcinoma (HCC) plays an important role in immune regulation and MDB pathogenesis. In this study, we conducted the first comprehensive study on cholangiocyte heterogeneity to demonstrate the pathogenesis of MDBs formation using single-nucleus RNA sequencing (snRNA-seq) from fractionations of normal and DDC-treated mouse livers. We found that cholangiocytes in the MDB-forming groups were significantly expanded, and the enrichment pathways of differentially expressed genes (DEGs) were markedly involved in metabolic processes, neurodegenerative diseases, autophagy, and ubiquitin-mediated proteolysis. We proposed a cellular-state landscape for cholangiocytes using uniform manifold approximation and projection (UMAP) analysis, which includes numerous cell subpopulations, referred to as Clusters0 through 7, with Cluster1 being the sole subpopulation made up entirely of DDC-treated cells. UbD was highly expressed in Cluster4 and colocalized with the cholangiocyte marker gene cytokeratin 19 (Krt19), implying that cholangiocytes function as facultative liver progenitor cells (LPCs) to supply damaged hepatocytes to promote MDBs formation. In summary, we revealed, for the first time, the heterogeneity of cholangiocytes and provided a novel viewpoint for understanding the mechanism of MDBs formation as well as chronic liver disease progression.
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Project description:Proteins which interact with IkBa in insoluble aggregates known as Mallory-Denk bodies were characterized by AP-MS, Biotinylation by antibody recognition (BAR), and LCMS analysis of detergent solubalized aggregates. See the supplementary table (S12) for file annotation.
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Project description:The whole rat genome microarray expression profiling of carotid artery specimen was emplyed to identify the gene expression profile before and after balloon injury. In our study, the neointimal formation of carotid arteries was apparent at day 7 and markedly increased at day 21 after balloon injury. In order to investigate the underlying mechanism of neointimal formationin in injured carotid arteries, all genes involved in signaling pathways whose expression was altered 2-fold in injured carotid arteries at day 7 and day 21 as compared to uninjured arteries were filtered out. Expression of four genes (TLR4, IRAK1, IκBα, IL-1β) from TLR signaling pathway was quantified in the same RNA samples by quantitative real-time PCR, conforming that TLR signaling pathway participated in neointimal formation of carotid arteries after balloon injury.
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Project description:The lack of a preclinical model of nonalcoholic steatohepatitis (NASH) and hepatocellular cancer (HCC) that recapitulates human disease is a major barrier to therapeutic development. We report a high fat-high sugar diet-induced NASH and HCC in a stable isogenic 129S1/SvImJ crossed with C57Bl/6J mice. Following diet initiation, there was sequential development of steatosis (4-8 weeks), steatohepatitis with ballooning and Mallory-Denk bodies (12-16 weeks), progressive fibrosis (16 week onwards) and spontaneous HCC (32-52 weeks). The mice developed obesity, insulin resistance and dyslipidemia. There was concordance with the human NASH transcriptome (FDR 0.001) with activation of lipogenic, inflammatory and apoptotic pathways relevant in humans. The HCC gene signature resembled S1 and S2 human HCC subclass (FDR 0.01 for both). This simple model of NASH and HCC that resembles human disease in terms of its triggers, physiological and biochemical parameters, histology, transcriptomic profile, and outcomes can facilitate preclinical development for these conditions.
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