Stem cell–derived models to improve mechanistic understanding and prediction of human drug-induced liver injury

Christopher Goldring; Daniel J. Antoine; Frank Bonner; Jonathan Crozier; Chris Denning; Robert J. Fontana; Neil A. Hanley; David C. Hay; Magnus Ingelman-Sundberg; Satu Juhila; Neil Kitteringham; Beatriz Silva-Lima; Alan Norris; Chris Pridgeon; James A. Ross; Rowena Sison Young; Danilo Tagle; Belen Tornesi; Bob van de Water; Richard J. Weaver; Fang Zhang; B. Kevin Park

doi:10.1002/hep.28886

Stem cell–derived models to improve mechanistic understanding and prediction of human drug-induced liver injury

Christopher Goldring^*, Daniel J. Antoine, Frank Bonner, Jonathan Crozier, Chris Denning, Robert J. Fontana, Neil A. Hanley, David C. Hay, Magnus Ingelman-Sundberg, Satu Juhila, Neil Kitteringham, Beatriz Silva-Lima, Alan Norris, Chris Pridgeon, James A. Ross, Rowena Sison Young, Danilo Tagle, Belen Tornesi, Bob van de Water, Richard J. WeaverFang Zhang, B. Kevin Park

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

50 Citations (Scopus)

Abstract

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. (Hepatology 2017;65:710-721).

Original language	English
Pages (from-to)	710-721
Number of pages	12
Journal	Hepatology
Volume	65
Issue number	2
DOIs	https://doi.org/10.1002/hep.28886
Publication status	Published - 1 Feb 2017

Bibliographical note

Funding Information:
Supported by the Medical Research Council (MR/L006758/1) and the European Community under the Innovative Medicine Initiative project MIPDILI (115336, to C.G., D.J.A., N.K., A.N., C.P., R.S.Y., F.Z., B.K.P.); Stem Cells for Safer Medicines (to F.B.); the Engineering and Physical Sciences Research Council, British Heart Foundation, Heart Research UK, the Medical Research Council, and the National Centre for the Replacement, Refinement and Reduction of Animals in Research (to C.D.); the Wellcome Trust and Stem Cells for Safer Medicines (to N.A.H.); the Innovative Medicines Initiative Joint Undertaking (115439, to J.R.), resources of which are composed of the financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies in-kind contributions; The Swedish Research Council and the European Community under the Innovative Medicine Initiative project MIP-DILI (115336, to M.I.-S.); and the EC FP7 project DETECTIVE (266838), the Innovative Medicine Initiative MIP-DILI project (115336), and the Horizon2020 EU-ToxRisk project (681002, to B.v.d.W.). R.J.F. is a member of the Drug-Induced Liver Injury Network, a U01 cooperative agreement supported by the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK065184).

Publisher Copyright:
© 2016 by the American Association for the Study of Liver Diseases.

ASJC Scopus subject areas

Hepatology

Access to Document

10.1002/hep.28886

Cite this

Goldring, C., Antoine, D. J., Bonner, F., Crozier, J., Denning, C., Fontana, R. J., Hanley, N. A., Hay, D. C., Ingelman-Sundberg, M., Juhila, S., Kitteringham, N., Silva-Lima, B., Norris, A., Pridgeon, C., Ross, J. A., Young, R. S., Tagle, D., Tornesi, B., van de Water, B., ... Park, B. K. (2017). Stem cell–derived models to improve mechanistic understanding and prediction of human drug-induced liver injury. Hepatology, 65(2), 710-721. https://doi.org/10.1002/hep.28886

@article{d12030079990480e8be7753067732cc5,

title = "Stem cell–derived models to improve mechanistic understanding and prediction of human drug-induced liver injury",

abstract = "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. (Hepatology 2017;65:710-721).",

author = "Christopher Goldring and Antoine, {Daniel J.} and Frank Bonner and Jonathan Crozier and Chris Denning and Fontana, {Robert J.} and Hanley, {Neil A.} and Hay, {David C.} and Magnus Ingelman-Sundberg and Satu Juhila and Neil Kitteringham and Beatriz Silva-Lima and Alan Norris and Chris Pridgeon and Ross, {James A.} and Young, {Rowena Sison} and Danilo Tagle and Belen Tornesi and {van de Water}, Bob and Weaver, {Richard J.} and Fang Zhang and Park, {B. Kevin}",

note = "Funding Information: Supported by the Medical Research Council (MR/L006758/1) and the European Community under the Innovative Medicine Initiative project MIPDILI (115336, to C.G., D.J.A., N.K., A.N., C.P., R.S.Y., F.Z., B.K.P.); Stem Cells for Safer Medicines (to F.B.); the Engineering and Physical Sciences Research Council, British Heart Foundation, Heart Research UK, the Medical Research Council, and the National Centre for the Replacement, Refinement and Reduction of Animals in Research (to C.D.); the Wellcome Trust and Stem Cells for Safer Medicines (to N.A.H.); the Innovative Medicines Initiative Joint Undertaking (115439, to J.R.), resources of which are composed of the financial contribution from the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies in-kind contributions; The Swedish Research Council and the European Community under the Innovative Medicine Initiative project MIP-DILI (115336, to M.I.-S.); and the EC FP7 project DETECTIVE (266838), the Innovative Medicine Initiative MIP-DILI project (115336), and the Horizon2020 EU-ToxRisk project (681002, to B.v.d.W.). R.J.F. is a member of the Drug-Induced Liver Injury Network, a U01 cooperative agreement supported by the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK065184). Publisher Copyright: {\textcopyright} 2016 by the American Association for the Study of Liver Diseases.",

year = "2017",

month = feb,

day = "1",

doi = "10.1002/hep.28886",

language = "English",

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Goldring, C, Antoine, DJ, Bonner, F, Crozier, J, Denning, C, Fontana, RJ, Hanley, NA, Hay, DC, Ingelman-Sundberg, M, Juhila, S, Kitteringham, N, Silva-Lima, B, Norris, A, Pridgeon, C, Ross, JA, Young, RS, Tagle, D, Tornesi, B, van de Water, B, Weaver, RJ, Zhang, F & Park, BK 2017, 'Stem cell–derived models to improve mechanistic understanding and prediction of human drug-induced liver injury', Hepatology, vol. 65, no. 2, pp. 710-721. https://doi.org/10.1002/hep.28886

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T1 - Stem cell–derived models to improve mechanistic understanding and prediction of human drug-induced liver injury

AU - Goldring, Christopher

AU - Antoine, Daniel J.

AU - Bonner, Frank

AU - Crozier, Jonathan

AU - Denning, Chris

AU - Fontana, Robert J.

AU - Hanley, Neil A.

AU - Hay, David C.

AU - Ingelman-Sundberg, Magnus

AU - Juhila, Satu

AU - Kitteringham, Neil

AU - Silva-Lima, Beatriz

AU - Norris, Alan

AU - Pridgeon, Chris

AU - Ross, James A.

AU - Young, Rowena Sison

AU - Tagle, Danilo

AU - Tornesi, Belen

AU - van de Water, Bob

AU - Weaver, Richard J.

AU - Zhang, Fang

AU - Park, B. Kevin

N1 - Funding Information: Supported by the Medical Research Council (MR/L006758/1) and the European Community under the Innovative Medicine Initiative project MIPDILI (115336, to C.G., D.J.A., N.K., A.N., C.P., R.S.Y., F.Z., B.K.P.); Stem Cells for Safer Medicines (to F.B.); the Engineering and Physical Sciences Research Council, British Heart Foundation, Heart Research UK, the Medical Research Council, and the National Centre for the Replacement, Refinement and Reduction of Animals in Research (to C.D.); the Wellcome Trust and Stem Cells for Safer Medicines (to N.A.H.); the Innovative Medicines Initiative Joint Undertaking (115439, to J.R.), resources of which are composed of the financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations companies in-kind contributions; The Swedish Research Council and the European Community under the Innovative Medicine Initiative project MIP-DILI (115336, to M.I.-S.); and the EC FP7 project DETECTIVE (266838), the Innovative Medicine Initiative MIP-DILI project (115336), and the Horizon2020 EU-ToxRisk project (681002, to B.v.d.W.). R.J.F. is a member of the Drug-Induced Liver Injury Network, a U01 cooperative agreement supported by the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK065184). Publisher Copyright: © 2016 by the American Association for the Study of Liver Diseases.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - 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. (Hepatology 2017;65:710-721).

AB - 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. (Hepatology 2017;65:710-721).

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DO - 10.1002/hep.28886

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ER -

Stem cell–derived models to improve mechanistic understanding and prediction of human drug-induced liver injury

Abstract

Bibliographical note

ASJC Scopus subject areas

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