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 personalised toxicology to determine inter-individual susceptibility to adverse drug reactions. However, the complexity of idiosyncratic drug-induced liver injury (DILI) 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 DILI. 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.

Comparative transcriptomics of hepatic differentiation of human pluripotent stem cells and adult human liver tissue

“…hPSC-HEP have the potential to be such a source (1,7,15,18,55,58) and possibly replace current hepatic models lacking adequate properties. However, for some applications the functionality of hPSC-HEP still needs to be further improved (15,25,37,42,48,56).…”

“…However, the shortage of donor organs requires the search for alternative treatments such as hepatocyte transplantation and extra corporeal liver application (16,23,49). Freshly isolated human hepatocytes are currently the gold standard cell type for transplantation as well as for cell modeling for drug discovery and development, and various toxicity tests (15,16,21,25,34). However, limited availability, short life span, loss of functionality upon isolation and culturing in vitro, dedifferentiation, and failing to represent the polymorphic population urge the development of alternative cell sources that do not have these drawbacks (15,25,31,34).…”

“…Improvements of the differentiation process of stem cells into hPSC-HEP have been achieved gradually in the last few years; however, methodology to generate fully functional hPSC-HEP is still lacking (9,15,23,25,42). The breakthrough of differentiating stem cells into hPSC-HEP with some activity of drug metabolic enzymes was accomplished by mimicking hepatogenesis in vitro (1,7,18,58).…”

Application of porcine gastrointestinal organoid units as a potential in vitro tool for drug discovery and development

“…Findings from a species similar to humans will be an invaluable resource with which to ascertain the validity and reliability of in vitro results before extrapolating and advancing to clinical studies. Improving the translational relevance of in vitro cell-based systems in drug-screening and development will address major health concerns for clinicians and drug companies, such as adverse drug reactions, a significant clinical problem resulting in a high rate of patient morbidity and mortality, along with huge financial implications (Goldring et al, 2017). Notably, an adverse drug reaction is a major contributor to drug attrition and withdrawal of potentially valuable drugs post-licensing.…”

Innovation for hepatotoxicity in vitro research models: A review

“…No studies using ESCs have successfully derived HLCs with adequate CYP activity in response to known reference compounds. It is clear that ESCs/HLCs are not currently sufficiently mature to emulate adult human PHs, and these cells are probably closer to fetal hepatocytes in phenotype (Goldring et al, ; Kia et al, ; Li et al, ).…”