Journal
HEPATOLOGY
Volume 65, Issue 2, Pages 710-721Publisher
WILEY
DOI: 10.1002/hep.28886
Keywords
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Categories
Funding
- Medical Research Council [MR/L006758/1]
- European Community under the Innovative Medicine Initiative project MIP-DILI [115336]
- Stem Cells for Safer Medicines
- Engineering and Physical Sciences Research Council
- British Heart Foundation
- Heart Research UK
- Medical Research Council
- Refinement and Reduction of Animals in Research
- Wellcome Trust and Stem Cells for Safer Medicines
- Innovative Medicines Initiative Joint Undertaking [115439]
- European Union's Seventh Framework Programme (FP7)
- European Federation of Pharmaceutical Industries and Associations companies in-kind contributions
- Swedish Research Council
- EC FP7 project DETECTIVE [266838]
- Innovative Medicine Initiative MIP-DILI project [115336]
- Horizon2020 EU-ToxRisk project [681002]
- National Institute of Diabetes and Digestive and Kidney Diseases [U01DK065184]
- BBSRC [BB/G021821/1, BB/E006159/1] Funding Source: UKRI
- EPSRC [DT/E005039/2] Funding Source: UKRI
- MRC [MR/L006758/1, G0700654, G0801098, MR/L022974/1, G113/30, MR/K026666/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E006159/1, BBS/B/06164, BB/G021821/1] Funding Source: researchfish
- British Heart Foundation [SP/15/9/31605, PG/09/027/27141, PG/14/59/31000] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [DT/E005039/2] Funding Source: researchfish
- Heart Research UK [RG2616] Funding Source: researchfish
- Medical Research Council [G0700654, MR/L006758/1, MR/K026666/1, MR/L022974/1, 1610737, G0801098, G113/30] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [NC/K000225/1, NC/C013202/1, NC/C013105/1] Funding Source: researchfish
- The British Council [04BX14CDLG] Funding Source: researchfish
Ask authors/readers for more resources
Current preclinical drug testing does not predict some forms of adverse drug reactions in humans. Efforts at improving predictability of drug- induced tissue injury in humans include using stem cell technology to generate human cells for screening for adverse effects of drugs in humans. The advent of induced pluripotent stem cells means that it may ultimately be possible to develop personalized toxicology to determine interindividual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury means that no current single-cell model, whether of primary liver tissue origin, from liver cell lines, or derived from stem cells, adequately emulates what is believed to occur during human drug-induced liver injury. Nevertheless, a single-cell model of a human hepatocyte which emulates key features of a hepatocyte is likely to be valuable in assessing potential chemical risk; furthermore, understanding how to generate a relevant hepatocyte will also be critical to efforts to build complex multicellular models of the liver. Currently, hepatocyte-like cells differentiated from stem cells still fall short of recapitulating the full mature hepatocellular phenotype. Therefore, we convened a number of experts from the areas of preclinical and clinical hepatotoxicity and safety assessment, from industry, academia, and regulatory bodies, to specifically explore the application of stem cells in hepatotoxicity safety assessment and to make recommendations for the way forward. In this short review, we particularly discuss the importance of benchmarking stem cell- derived hepatocyte-like cells to their terminally differentiated human counterparts using defined phenotyping, to make sure the cells are relevant and comparable between labs, and outline why this process is essential before the cells are introduced into chemical safety assessment.
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