0000000000516205

AUTHOR

Magnus Ingelman-sundberg

showing 4 related works from this author

Three-Dimensional Spheroid Primary Human Hepatocytes in Monoculture and Coculture with Nonparenchymal Cells

2018

Recent advances in the development of various culture platforms are promising for achieving more physiologically relevant in vitro hepatic models using primary human hepatocytes (PHHs). Previous studies have shown the value of PHHs three-dimensional (3D) spheroid models, cultured in low cell number (1330-2000 cells/3D spheroid), to study long-term liver function as well as pharmacological drug effects and toxicity. In this study, we report that only plateable PHHs aggregate and form compact 3D spheroids with a success rate of 79%, and 96% reproducibility. Out of 3D spheroid forming PHH lots, 65% were considered stable (<50% ATP decrease) over the subsequent 14 days of culture, with reproduc…

0301 basic medicineTime FactorsCell SurvivalKupffer CellsCellCell Culture TechniquesBiomedical EngineeringMedicine (miscellaneous)BioengineeringCell SeparationCryopreservation03 medical and health sciencesAdenosine Triphosphate0302 clinical medicineSpheroids CellularmedicineHumansRNA MessengerCell ShapeCell AggregationCell SizeCryopreservationChemistrySpheroidAlbuminCoculture TechniquesIn vitroCell biology030104 developmental biologymedicine.anatomical_structureGene Expression Regulation030220 oncology & carcinogenesisHepatocytesHepatic stellate cellLiver functionBiomarkersImmunostainingTissue Engineering Part C: Methods
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Human Embryonic Stem Cell Derived Hepatocyte-Like Cells as a Tool for In Vitro Hazard Assessment of Chemical Carcinogenicity

2011

Hepatocyte-like cells derived from the differentiation of human embryonic stem cells (hES-Hep) have potential to provide a human relevant in vitro test system in which to evaluate the carcinogenic hazard of chemicals. In this study, we have investigated this potential using a panel of 15 chemicals classified as noncarcinogens, genotoxic carcinogens, and nongenotoxic carcinogens and measured whole-genome transcriptome responses with gene expression microarrays. We applied an ANOVA model that identified 592 genes highly discriminative for the panel of chemicals. Supervised classification with these genes achieved a cross-validation accuracy of > 95%. Moreover, the expression of the response g…

Carcinogenicity TestsCellular differentiationCell Culture TechniquesGene Expressionsystems toxicologyComputational biologyBiologyToxicologymedicine.disease_causeHazardous SubstancesTranscriptomecomputational biologyCytochrome P-450 Enzyme SystemNaturvetenskapmedicinecarcinogenicityHumansMicroscopy Phase-ContrastEmbryonic Stem CellsCarcinogenAnalysis of VarianceDose-Response Relationship DrugReverse Transcriptase Polymerase Chain ReactionMicroarray analysis techniquesGene Expression ProfilingReproducibility of Resultsrisk assessmentCell DifferentiationMicroarray AnalysisImmunohistochemistryEmbryonic stem cellMolecular biologyGene expression profilingCell culturetoxicogenomicsCarcinogensHepatocytesNatural SciencesCarcinogenesisToxicological Sciences
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Inter-individual differences in the susceptibility of primary human hepatocytes towards drug-induced cholestasis are compound and time dependent.

2018

Abstract Cholestasis represents a major subtype of drug-induced liver injury and novel preclinical models for its prediction are needed. Here we used primary human hepatocytes (PHH) from different donors in 2D-sandwich (2D-sw) and/or 3D-spheroid cultures to study inter-individual differences in the response towards cholestatic hepatotoxins after short-term (48–72 hours) and long-term repeated exposures (14 days). The cholestatic liabilities of drugs were determined by comparing cell viability upon exposure to the highest non-cytotoxic drug concentration in the presence and absence of a non-cytotoxic concentrated bile acid mixture. In 2D-sw culture, cyclosporine A and amiodarone presented cl…

0301 basic medicineMaleTime Factorsmedicine.drug_classPrimary Cell CulturePharmacologyToxicologyRisk Assessment03 medical and health sciencesCholestasisSpheroids CellularmedicineHumansChlorpromazineCells CulturedAgedLiver injuryCholestasisBile acidDose-Response Relationship Drugbusiness.industryBile CanaliculiHepatotoxinTroglitazoneGeneral MedicineMiddle Agedmedicine.diseaseBosentan3. Good health030104 developmental biologyBiological Variation PopulationToxicityHepatocytesFemaleChemical and Drug Induced Liver Injurybusinessmedicine.drugToxicology letters
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Transcriptional Regulation of Human CYP3A4 Basal Expression by CCAAT Enhancer-Binding Protein α and Hepatocyte Nuclear Factor-3γ

2003

Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more than 50% of currently used therapeutic drugs, yet the mechanisms that control CYP3A4 basal expression in liver are poorly understood. Several putative binding sites for CCAAT/enhancer-binding protein (C/EBP) and hepatic nuclear factor 3 (HNF-3) were found by computer analysis in CYP3A4 promoter. The use of reporter gene assays, electrophoretic mobility shift assays, and site-directed mutagenesis revealed that one proximal and two distal C/EBP alpha binding sites are essential sites for the trans-activation of CYP3A4 promoter. No trans-activation was found in similar reporter gene experiments with a HNF-3 gamma expression vec…

Transcriptional ActivationTranscription GeneticGenetic VectorsBiologyTransfectiondigestive systemGene Expression Regulation EnzymologicChromatin remodelingAdenoviridaeCytochrome P-450 Enzyme SystemCCAAT-Enhancer-Binding Protein-alphamedicineCytochrome P-450 CYP3AHumansEnzyme InhibitorsBinding sitePromoter Regions GeneticCells CulturedPharmacologyReporter geneExpression vectorCcaat-enhancer-binding proteinsNuclear ProteinsMolecular biologyChromatinDNA-Binding ProteinsHistone Deacetylase InhibitorsHepatocyte nuclear factorsTrichostatin AHepatocytesMolecular MedicineHepatocyte Nuclear Factor 3-gammaTranscription Factorsmedicine.drugMolecular Pharmacology
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