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Organoids derived from directly reprogrammed human hepatocytes for modeling liver cancer initiation

ABSTRACT: Organoids derived from directly reprogrammed human hepatocytes for modeling liver cancer initiation

PROVIDER: PRJNA476313 | ENA |

REPOSITORIES: ENA

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Organoids derived from directly reprogrammed human hepatocytes for modeling liver cancer initiation

Project description:Hepatocellular carcinoma (HCC) and cholangiocarcinoma (ICC) are two main forms liver cancers with poor prognosis. Models for studying HCC and ICC development using human liver cells are urgently needed. Organoids serve as in vitro models for cancer studies as it recapitulates in vivo structures and microenvironment of solid tumors. Herein, we established liver cancer organoid models by introducing specific mutations into human induced hepatocyte (hiHep)-derived organoids. c-MYC and hRASG12V overexpression in hiHep organoids with repressed p53 activation by large T led to distinct HCC and ICC signatures. With these oncogenic mutations, the neoplastic hiHep organoids formed cancerous structures and possessed cancer-specific hallmarks. Comprehensive transcriptional analysis of liver cancer organoids revealed genes and pathways with disease-stage-specific alterations. Notably, with RAS mutations, hiHep organoids acquired biliary trans-differentiation, and showed a process of conversion from hepatocytes to ICC. To sum up, we have established a useful and convenient in vitro human organoid systems modeling liver cancer development.

2019-05-20 | GSE115853 | GEO

Metabolic characterization of directly reprogrammed renal tubular epithelial cells (iRECs)

Project description:Fibroblasts can be directly reprogrammed to induced renal tubular epithelial cells (iRECs) using four transcription factors. These engineered cells may be used for disease modeling, cell replacement therapy or drug and toxicity testing. Direct reprogramming induces drastic changes in the transcriptional landscape, protein expression, morphological and functional properties of cells. However, how the metabolome is changed by reprogramming and to what degree it resembles the target cell type remains unknown. Using untargeted gas chromatography-mass spectrometry (GC-MS) and targeted liquid chromatography-MS, we characterized the metabolome of mouse embryonic fibroblasts (MEFs), iRECs, mIMCD-3 cells, and whole kidneys. Metabolic fingerprinting can distinguish each cell type reliably, revealing iRECs are most similar to mIMCD-3 cells and clearly separate from MEFs used for reprogramming. Treatment with the cytotoxic drug cisplatin induced typical changes in the metabolic profile of iRECs commonly occurring in acute renal injury. Interestingly, metabolites in the medium of iRECs, but not of mIMCD-3 cells or fibroblast could distinguish treated and non-treated cells by cluster analysis. In conclusion, direct reprogramming of fibroblasts into renal tubular epithelial cells strongly influences the metabolome of engineered cells, suggesting that metabolic profiling may aid in establishing iRECs as in vitro models for nephrotoxicity testing in the future.

2021-08-20 | MTBLS608 | MetaboLights

Influence of Sox4 on transcriptomic changes in adult hepatocytes

Project description:Recent studies have demonstrated that hepatocytes can be reprogrammed into biliary epithelial cell-like cells. An earlier work in our laboratory nominated Sox4 as an initiation factor of this reprogramming event. To investigate the effect of Sox4 on the transcriptomic changes in hepatocytes, we performed RNA-seq of Sox4-overexpressed (OE) hepatocytes.

2023-11-28 | GSE218947 | GEO

Profiling histone post-translational modifications in mouse adult hepatocytes, biliary epithelial cells and biliary reprogrammed cells from hepatocytes.

Project description:Recent studies have demonstrated that hepatocytes can be reprogrammed into biliary epithelial cell-like cells under cholestatic liver injury. To investigate the changes in histone post-translational modification in hepatocyte-derived reprogramming cells, we performed Cleavage Under Targets and Tagmentation (CUT&Tag)-sequencing.

2024-01-31 | GSE237908 | GEO

Influence of Sox4 on chromatin accessibility of adult hepatocytes

Project description:Recent studies have demonstrated that hepatocytes can be reprogrammed into biliary epithelial cell-like cells. An earlier work in our laboratory nominated Sox4 as an initiation factor of this reprogramming event To investigate the effect of Sox4 on the change of chromatin landscape of hepatocytes, we performed ATAC-seq of Sox4-overexpressed (OE) hepatocytes.

2022-07-29 | GSE209556 | GEO

Directly Reprogrammed Human Neurons Identify a Pathogenic Mechanism of Valproic Acid at Early Developmental Stages

Project description:Human pluripotent stem cells can be rapidly converted into functional neurons by ectopic expression of proneural transcription factors. Here we show that directly reprogrammed neurons, despite their rapid maturation kinetics, can model teratogenic mechanisms that specifically affect early neurodevelopment. We delineated distinct phases of in vitro maturation during reprogramming of human neurons and assessed the cellular phenotypes of valproic acid (VPA), a teratogenic drug. VPA exposure caused chronic impairment of dendritic morphology and functional properties of developing neurons, but not those of mature neurons. These pathogenic effects were associated with VPA-mediated inhibition of the histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) pathways, which caused transcriptional downregulation of many genes, including MARCKSL1, an actin-stabilizing protein essential for dendritic morphogenesis and synapse maturation during early neurodevelopment. Our findings identify a developmentally restricted pathogenic mechanism of VPA and establish the use of reprogrammed neurons as an effective platform for modeling teratogenic pathways.

2019-05-28 | GSE129241 | GEO

Influence of Sox4 on chromatin accessibility of adult hepatocytes II

Project description:Recent studies have demonstrated that hepatocytes can be reprogrammed into biliary epithelial cell-like cells. An earlier work in our laboratory nominated Sox4 as an initiation factor of this reprogramming event To investigate the effect of Sox4 on the change of chromatin landscape of hepatocytes, we performed ATAC-seq of exogenously Sox4-expressed hepatocytes.

2024-01-27 | GSE253988 | GEO

Influence of Sox4 on chromatin accessibility of adult hepatocytes [EV and Sox4]

Project description:Recent studies have demonstrated that hepatocytes can be reprogrammed into biliary epithelial cell-like cells. An earlier work in our laboratory nominated Sox4 as an initiation factor of this reprogramming event To investigate the effect of Sox4 on the change of chromatin landscape of hepatocytes, we performed ATAC-seq of exogenously Sox4-expressed hepatocytes.

2023-11-28 | GSE219052 | GEO

Transcriptional profiling of hepatocyte, reprogrammed hepatocyte, and biliary cells [human]

Project description:Comparison of transcripts between human hepatocytes, human hepatocytes reprogrammed into biliary cells, and human biliary cells shows similarities between reprogrammed cells and the untreated biliary population

2020-09-09 | GSE157661 | GEO

Autophagy impairments in directly reprogrammed neurons in patients with idiopathic Parkinson’s disease

Project description:Protein degradation impairment is strongly suspected to play a role in idiopathic Parkinson’s disease (PD). However, current tools and models are lacking to study such disease associated phenotypes across the PD patient population. Here, we generate functional induced dopaminergic neurons (iDANs) directly reprogrammed from adult dermal fibroblasts of patients with PD to investigate intra-neuronal autophagy alterations.

2019-06-01 | GSE125239 | GEO

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