Bulk RNA sequencing analysis of hepatocytes isolated from humanized liver
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE234757 | GEO | 2023/06/16
REPOSITORIES: GEO
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Project description:Single cell RNA sequencing of liver cells enriched for Non-Parenchymal cells (NPCs) to see the percentage of humanizaton, the gene signature and the heterogeneity of most types of human NPCs in a humanized liver.
2023-06-16 | GSE234758 | GEO
Project description:Background & Aims: Since the first account of the myth of Prometheus, the amazing regenerative capacity of the liver has fascinated researchers due to its enormous medical potential. Liver regeneration is promoted by multiple types of liver cells, including hepatocytes and liver non-parenchymal cells (NPCs), through the complex intercellular signaling. However, the liver organogenetic mechanism, especially the role of adult hepatocytes at ectopic sites, remains unknown. In this study, we demonstrate that hepatocytes alone spurred liver organogenesis to form an organ-sized complex 3D liver that exhibited native liver architecture and functions in the kidneys of mice. Methods: Isolated hepatocytes were transplanted under the kidney capsule of monocrotaline (MCT) and partial hepatectomy (PHx)-treated mice. To determine the origin of NPCs in neo-livers, hepatocytes were transplanted into MCT/PHx-treated green fluorescent protein (GFP) transgenic mice or wild-type mice transplanted with bone marrow (BM) cells isolated from GFP mice. Results: Hepatocytes engrafted at the subrenal space of mice underwent continuous growth in response to a chronic hepatic injury in the native liver. More than 1.5 yrs later, whole organ-sized liver tissues having a greater mass than those of the injured native liver had formed. Most remarkably, we revealed that at least three types of NPCs with similar phenotypic features to the liver NPCs were recruited from the host tissues including BM. The neo-livers in the kidney exhibited liver-specific functions and architectures, including sinusoidal vascular systems, zonal heterogeneity, and emergence of bile duct cells. Furthermore, the neo-livers successfully rescued the mice with lethal liver injury. Conclusion: Our data clearly showed that adult hepatocytes play a leading role as organizer cells in liver organogenesis at ectopic sites via NPC recruitment.
2017-12-25 | GSE99141 | GEO
Project description:The human liver functions through a complex interplay of parenchymal and non-parenchymal cells, which participate in performing many essential aspects of metabolism and secretion. Mass spectrometry-based proteomic analysis of intact tissue has improved the understanding of these processes, by providing an in-depth view of the human liver proteome. However, the predominance of parenchymal cells, i.e. hepatocytes, means that the total tissue proteome mainly reflects hepatocyte expression. In this study, we therefore used quantitative label-free proteomic analysis to analyze the proteomes of the major parenchymal and non-parenchymal cell types in the human liver, i.e. hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells. We found that our data recapitulated specific functional differences between cell types, meaning that it can be used to reliably probe various aspects of cellular interplay. Thus, the data we provide constitutes a unique resource for exploring the human liver proteome at major cell type resolution.
2020-04-09 | PXD012615 | Pride
Project description:Human hepatocyte chimeric mice were prepared and treated with hepatitis C virus (HCV) and/or interferon-alpha (IFN-α). To analyze the changes in gene expression, cDNA microarray analysis was performed with the collected human hepatocytes from the chimeric mouse livers. We consider that these results provide molecular insights into possible mechanisms used by HCV to evade innate immune responses, as well as novel therapeutic targets and a potential new indication for interferon therapy. A total of 15 human hepatocyte chimeric mice were prepared and divided into four experimental groups. Mice in group A were neither infected with HCV nor treated with IFN. Mice in group B were administered IFN-α 6 h before sacrifice but were not infected with HCV. The mice in groups C and D were both inoculated via the mouse tail vein with human serum containing HCV genotype 1b particles. At 8 weeks after inoculation, the mice in group D were administered IFN-α 6 h before sacrifice, but the mice in group C were not treated with IFN-α. The human hepatocytes in the mouse livers were collected after sacrifice and subjected to microarray analysis. After purification and reverse transcription of total RNA, cDNA was hybridized on Affymetrix GeneChip Human Gene U133 Plus 2.0 Arrays.
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Project description:The goal of this experiment was to test whether human hepatocytes could give rise to biliary-like progenitor cells in an in vivo context. Here Fah-/- Il2ry-/- Rag2-/-NOD mouse livers were humanized with human hepatocytes. Only hepatocytes engraft in the Fah-/- mouse at detectable levels in this model. Then animals were given chronic liver injury with 0.1% ddc. After injury we measured human-specific transcripts to determine whether the phenotype of the human cells had changed. Specifically, we evaluated the relative levels of human biliary duct markers such as Spp1, Sox9, Krt7, etc. and hepatocyte markers such as Alb, Ttr, Fah, etc. 3 DDC treated chimeras and 6 untreated chimeras are included. Additional controls include a normal human liver biopsy, FACS sorted primary intrahepatic human bile duct cells, mouse hepatocytes, and mouse intrahepatic biliary cells in ddc treated animal.
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Project description:Rhythmic intraorgan communication coordinates environmental signals and cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific knockout of core components of the molecular clock, Rev-erba and b (ReverbhDKO), alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in non-parenchymal cells (NPC) of the liver. Here we report that in diet induced obesity (DIO)-caused fatty liver, hepatocyte SREBP cleavage-activating protein (SCAP) is required for ReverbhDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in Kupffer cells (KC). Integrative analyses of isolated hepatocytes and Kupffer cells uncovered potential signals, including secreted polypeptides and metabolites, that gain rhythmicity in the absence of REV-ERBs in a SCAP-dependent manner. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in DIO and fatty liver disease.
2023-04-04 | GSE206316 | GEO
Project description:Rhythmic intraorgan communication coordinates environmental signals and cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific knockout of core components of the molecular clock, Rev-erba and b (ReverbhDKO), alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in non-parenchymal cells (NPC) of the liver. Here we report that in diet induced obesity (DIO)-caused fatty liver, hepatocyte SREBP cleavage-activating protein (SCAP) is required for ReverbhDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in Kupffer cells (KC). Integrative analyses of isolated hepatocytes and Kupffer cells uncovered potential signals, including secreted polypeptides and metabolites, that gain rhythmicity in the absence of REV-ERBs in a SCAP-dependent manner. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in DIO and fatty liver disease.
2023-04-04 | GSE206318 | GEO
Project description:Rhythmic intraorgan communication coordinates environmental signals and cell-intrinsic clock to maintain organ homeostasis. Hepatocyte-specific knockout of core components of the molecular clock, Rev-erba and b (ReverbhDKO), alters cholesterol and lipid metabolism in hepatocytes as well as rhythmic gene expression in non-parenchymal cells (NPC) of the liver. Here we report that in diet induced obesity (DIO)-caused fatty liver, hepatocyte SREBP cleavage-activating protein (SCAP) is required for ReverbhDKO-induced diurnal rhythmic remodeling and epigenomic reprogramming in Kupffer cells (KC). Integrative analyses of isolated hepatocytes and Kupffer cells uncovered potential signals, including secreted polypeptides and metabolites, that gain rhythmicity in the absence of REV-ERBs in a SCAP-dependent manner. These results shed light on the signaling mechanisms by which hepatocytes regulate diurnal rhythms in NPCs in DIO and fatty liver disease.
2023-04-04 | GSE206317 | GEO
Project description:Hepatocytes isolated from DILI patient's liver (#2064) were cultured for a long term using irrMEF and EMUKK-05, and comprehensive gene expression was compared between Puromycin-treated and non-treated groups. In addition, comprehensive gene expression analysis of human mature hepatocytes, primary cultured cells, and ips cell-derived hepatocyte-like cells were performed as controls. Two-condition experiment, Proliferating hepatocytes (ProilHH) vs. puromycin-treated ProliHH. Primary human hepatocytes (PHH) and isolated humen mature hepatocytes (MH) and human iPSC-derived hepatocyte-like cells (HLC) as controls.
2021-12-30 | GSE192653 | GEO
Project description:Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, since rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling, and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/ß-catenin signaling when compared to those of hCAR/hPXR mice, wild type mice and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators, whereas the hCAR/hPXR mouse is not.
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