Systematic transcriptome-based comparison of cellular adaptive stress response activation networks in hepatic stem cell-derived progeny and primary human hepatocytes

Toxicology in Vitro, vol. 73, pp. 105107

Abstract

Various adaptive cellular stress response pathways are critical in the pathophysiology of liver disease and drug-induced liver injury. Human-induced pluripotent stem cell (hiPSC)-derived hepatocyte-like cells (HLCs) provide a promising tool to study cellular stress response pathways, but in this context there is limited insight on how HLCs compare to other in vitro liver models. Here, we systematically compared the transcriptomic profiles upon chemical activation in HLCs, hiPSC, primary human hepatocytes (PHH) and HepG2 liver cancer cells. We used targeted RNA-sequencing to map concentration transcriptional response using benchmark concentration modeling for the various stress responses in the different test systems. We found that HLCs are very sensitive towards oxidative stress and inflammation conditions as corresponding genes were activated at over 3 fold lower concentrations of the corresponding pathway inducing compounds as compared to PHH. PHH were the most sensitive model when studying UPR related effects. Due to the non-proliferative nature of PHH and HLCs, these do not pose a good/sensitive model to pick up DNA damage responses, while hiPSC and HepG2 were more sensitive in these conditions. We envision that this study contributes to a better understanding on how HLCs can contribute to the assessment of cell physiological stress response activation to predict hepatotoxic events.

Authors 10

1. Bas ter Braak Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands

2. Marije Niemeijer Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands

3. Ruben Boon

   Leuven Stem Cell Institute · KU Leuven

   Affiliation as printed

   Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium

4. Celine Parmentier
   Affiliation as printed

   KaLy-Cell, Plobsheim, France

5. Audrey Baze
   Affiliation as printed

   KaLy-Cell, Plobsheim, France

6. Lysiane Richert
   Affiliation as printed

   KaLy-Cell, Plobsheim, France

7. Suzanna Huppelschoten Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands

8. Steven Wink Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands

9. Catherine M. Verfaillie

   Leuven Stem Cell Institute · KU Leuven

   Affiliation as printed

   Department of Development and Regeneration, Stem Cell Institute, KU Leuven, Leuven, Belgium

10. Bob van de Water corresponding Aachen Division of Drug Discovery and Safety Leiden Academic Centre for Drug Research

    Leiden University

    Affiliation as printed

    Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands. Electronic address: b.water@lacdr.leidenuniv.nl

    Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands