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Robust Generation of Hepatocyte-like Cells from Human Embryonic Stem Cell Populations
Published on: October 26, 2011
HiPSC-Derived Hepatocyte-like Cells Can Be Used as a Model for Transcriptomics-Based Study of Chemical Toxicity
Sreya Ghosh1, Jonathan De Smedt1, Tine Tricot1
1Department of Development and Regeneration, Stem Cell Institute, KU Leuven, 3000 Leuven, Belgium.
Abstract:
Traditional toxicity risk assessment approaches have until recently focussed mainly on histochemical readouts for cell death. Modern toxicology methods attempt to deduce a mechanistic understanding of pathways involved in the development of toxicity, by using transcriptomics and other big data-driven methods such as high-content screening. Here, we used a recently described optimised method to differentiate human induced pluripotent stem cells (hiPSCs) to hepatocyte-like cells (HLCs), to assess their potential to classify hepatotoxic and non-hepatotoxic chemicals and their use in mechanistic toxicity studies. The iPSC-HLCs could accurately classify chemicals causing acute hepatocellular injury, and the transcriptomics data on treated HLCs obtained by TempO-Seq technology linked the cytotoxicity to cellular stress pathways, including oxidative stress and unfolded protein response (UPR). Induction of these stress pathways in response to amiodarone, diclofenac, and ibuprofen, was demonstrated to be concentration and time dependent. The transcriptomics data on diclofenac-treated HLCs were found to be more sensitive in detecting differentially expressed genes in response to treatment, as compared to existing datasets of other diclofenac-treated in vitro hepatocyte models. Hence iPSC-HLCs generated by transcription factor overexpression and in metabolically optimised medium appear suitable for chemical toxicity detection as well as mechanistic toxicity studies.
Insights
Human induced pluripotent stem cell-derived hepatocyte-like cells (hiPSC-HLCs) effectively identify toxic chemicals and reveal cellular stress mechanisms. This advanced method offers a sensitive approach for both toxicity classification and mechanistic studies in toxicology.
Area of Science:
- Hepatocyte-like cell differentiation
- Toxicology
- Transcriptomics
Background:
- Traditional toxicity assessments rely on cell death readouts.
- Modern toxicology utilizes transcriptomics for mechanistic insights.
- Human induced pluripotent stem cells (hiPSCs) offer a promising source for in vitro models.
Purpose of the Study:
- To assess the utility of hiPSC-derived hepatocyte-like cells (HLCs) for classifying hepatotoxic chemicals.
- To investigate the mechanistic pathways of chemical toxicity using transcriptomics.
- To compare the sensitivity of hiPSC-HLCs with existing in vitro hepatocyte models.
Main Methods:
- Differentiation of hiPSCs into HLCs using an optimized method.
- Treatment of hiPSC-HLCs with known hepatotoxic and non-hepatotoxic chemicals.
- Analysis of transcriptomic changes using TempO-Seq technology.
- Assessment of cytotoxicity and pathway activation (oxidative stress, unfolded protein response).
Main Results:
- hiPSC-HLCs accurately classified chemicals causing acute hepatocellular injury.
- Transcriptomics data linked cytotoxicity to cellular stress pathways, including oxidative stress and unfolded protein response (UPR).
- Stress pathway induction was concentration and time-dependent for amiodarone, diclofenac, and ibuprofen.
- Diclofenac treatment showed more sensitive gene expression changes in hiPSC-HLCs compared to other models.
Conclusions:
- hiPSC-HLCs are suitable for chemical toxicity detection.
- This model aids in mechanistic toxicity studies by identifying activated cellular pathways.
- The optimized hiPSC-HLC differentiation method enhances sensitivity in toxicity assessments.
