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Research ArticleArticle

Transcriptional, functional and mechanistic comparisons of stem cell-derived hepatocytes, HepaRG cells and 3D human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury

Catherine C Bell, Volker M Lauschke, Sabine U Vorrink, Henrik Palmgren, Roger Duffin, Tommy B Andersson and Magnus Ingelman-Sundberg
Drug Metabolism and Disposition January 30, 2017, dmd.116.074369; DOI: https://doi.org/10.1124/dmd.116.074369
Catherine C Bell
1 Karolinska Institutet;
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Volker M Lauschke
1 Karolinska Institutet;
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  • ORCID record for Volker M Lauschke
  • For correspondence: volker.lauschke@ki.se
Sabine U Vorrink
1 Karolinska Institutet;
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Henrik Palmgren
2 AstraZeneca;
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Roger Duffin
3 CXR Biosciences
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Tommy B Andersson
2 AstraZeneca;
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Magnus Ingelman-Sundberg
1 Karolinska Institutet;
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Abstract

Reliable and versatile hepatic in vitro systems for the prediction of drug pharmacokinetics and toxicity are essential constituents of preclinical safety assessment pipelines for new medicines. Here, we compared three emerging cell systems, hepatocytes derived from induced pluripotent stem cells (hiPS-Hep), HepaRG cells and 3D primary human hepatocyte (PHH) spheroids at transcriptional and functional levels in a multi-center study to evaluate their potential as predictive models for drug-induced hepatotoxicity. Transcriptomic analyses revealed widespread gene expression differences between the three cell models, with 8,148 out of 17,462 analyzed genes (47%) being differentially expressed. Expression levels of genes involved in the metabolism of endogenous as well as xenobiotic compounds were significantly elevated in PHH spheroids, whereas genes involved in cell division and endocytosis were significantly upregulated in HepaRG and hiPS-Hep cells, respectively. Consequently, PHH spheroids were more sensitive to a panel of drugs with distinctly different toxicity mechanisms, an effect that was amplified by long-term exposure using repeated treatments. Importantly, toxicogenomic analyses revealed that transcriptomic changes in PHH spheroids were in compliance with cholestatic, carcinogenic or steatogenic in vivo toxicity mechanisms at clinically relevant drug concentrations. Combined, the data reveal important phenotypic differences between the three cell systems and suggest that PHH spheroids can be used for functional investigations of drug-induced liver injury in vivo in man.

  • animal/nonclinical/preclinical
  • in vitro-in vivo prediction (IVIVE)
  • liver injury/toxicity (DILI)
  • liver/hepatic
  • stem cells
  • toxicology
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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Research ArticleArticle

Transcriptional, functional and mechanistic comparisons of stem cell-derived hepatocytes, HepaRG cells and 3D human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury

Catherine C Bell, Volker M Lauschke, Sabine U Vorrink, Henrik Palmgren, Roger Duffin, Tommy B Andersson and Magnus Ingelman-Sundberg
Drug Metabolism and Disposition January 30, 2017, dmd.116.074369; DOI: https://doi.org/10.1124/dmd.116.074369

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Research ArticleArticle

Transcriptional, functional and mechanistic comparisons of stem cell-derived hepatocytes, HepaRG cells and 3D human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury

Catherine C Bell, Volker M Lauschke, Sabine U Vorrink, Henrik Palmgren, Roger Duffin, Tommy B Andersson and Magnus Ingelman-Sundberg
Drug Metabolism and Disposition January 30, 2017, dmd.116.074369; DOI: https://doi.org/10.1124/dmd.116.074369
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