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Engineered Human Liver Cocultures for Investigating Drug-Induced Liver Injury

  • Chase P. Monckton
  • Salman R. Khetani
Protocol
Part of the Methods in Pharmacology and Toxicology book series (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.

Key words

Microfabrication Soft lithography Microfluidics Micropatterned cocultures Liver-on-a-chip Hepatocytes Nonparenchymal cells 3D liver spheroids 

Notes

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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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BioengineeringUniversity of Illinois at ChicagoChicagoUSA

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