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Drug-Induced Liver Toxicity pp 213–248Cite as

Engineered Human Liver Cocultures for Investigating Drug-Induced Liver Injury

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Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

Drug-induced liver injury (DILI) remains a major cause of drug attrition, black-box warnings on marketed drugs, and acute liver failures. It is clear with several high-profile drug failures that animal models do not suffice for predicting human DILI largely due to species-specific differences in drug metabolism pathways. Thus, in vitro models of the human liver are playing an ever-important role in mitigating DILI risk during preclinical testing. Methods to isolate and culture hepatocytes on collagen-coated plastic in the presence of supportive liver- and non-liver-derived nonparenchymal cell types (NPCs) were developed several decades ago; however, improvements were needed to stabilize diverse hepatic functions for several weeks to enable chronic drug treatment as in the clinic. Today, engineering tools such as protein micropatterning, microfluidics, specialized plates, biomaterial scaffolds, and bioprinting enable precise control over the cellular microenvironment for enhancing and stabilizing hepatic functions in the presence of NPC types, including those derived from the liver towards determining their impact on DILI progression. The introduction of induced pluripotent stem cell-derived human hepatocyte-like cells can potentially allow a better understanding of inter-individual differences in idiosyncratic DILI. Here, we review the abovementioned advances in the engineering of human liver cocultures and their utilization for predicting clinical DILI with high sensitivity/specificity and elucidating underlying mechanisms. Key platforms and associated validation data sets are presented to highlight major trends and pending issues to be addressed moving forward. In the future, engineered human liver cocultures will reduce drug attrition, animal usage, and cases of DILI in humans.

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Acknowledgments

The authors would like to thank Christine Lin and Brenton Ware for their helpful discussions. This work was funded by the National Institutes of Health (1R21ES027622-01 to S.R.K.). Salman R. Khetani is an equity holder in Ascendance Biotechnology, which has licensed the MPCC system from MIT and MPTC system from Colorado State University for commercial distribution.

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  1. Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA

    Chase P. Monckton & Salman R. Khetani

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  1. Chase P. Monckton
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  2. Salman R. Khetani
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Correspondence to Salman R. Khetani .

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  1. Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA

    Minjun Chen

  2. Drug Safety Research and Development, Pfizer Inc., Groton, CT, USA

    Yvonne Will

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Monckton, C.P., Khetani, S.R. (2018). Engineered Human Liver Cocultures for Investigating Drug-Induced Liver Injury. In: Chen, M., Will, Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-7677-5_11

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