Stem Cell Strategies to Evaluate Idiosyncratic Drug-induced Liver Injury

Abstract

The host-dependent nature of idiosyncratic drug-induced liver injury (iDILI) suggests that rare genetic polymorphisms may contribute to the disease. Indeed, a few mutations in key genes have already been identified using conventional human genetics approaches. Over 50 commonly used drugs can precipitate iDILI, making this a substantial medical problem. Only recently have human induced pluripotent stem cells been used as a research tool to discover novel iDILI genes and to study the mechanisms of iDILI in vitro. Here we review the current state of stem cell use in the investigation of iDILI, with a special focus on genetics. In addition, the concerns and difficulties associated with genetics and animal model research are discussed. We then present the features of patient-specific pluripotent stem cells (which may be derived from iDILI patients themselves), and explain why these cells may be of great utility. A variety of recent approaches to produce hepatocyte-like cells from pluripotent cells and the associated advantages and limitations of such cells are discussed. Future directions for the use of stem cell science to investigate iDILI include novel ways to identify new iDILI genes, a consideration of epigenetic impacts on iDILI, and the development of new and improved strategies for the production of hepatocytes from human pluripotent cells.

Keywords: DILI; Embryonic stem cell; Genetics; Toxicity; iPS.

Fig. 1. Strategy for using iPS reprogramming to investigate iDILI.

Somatic cell samples such as skin or blood are collected from iDILI and control patients. These are used to derive hiPSCs that are exact genetic matches to the donor patients. Such hiPSCs can be indefinitely expanded and passaged, so long as they are maintained under pluripotent conditions. hiPSCs can then be differentiated to iHLCs (hepatocyte-like cells). iHLCs from iDILI and control patients can then be compared using functional tests (A., such as exposure to the iDILI-precipitating drug) or using transcriptome comparisons (B.), which may lead to identification of iDILI genes. Subsequently, causative mutations (C.) can be identified, using transcriptome alterations as a guide.

Fig. 2. Determinants of susceptibility to drug-induced liver injury (DILI).

A number of patient-specific (idiosyncratic) factors greatly modulate the sensitivity to the potential hepatotoxic effects of certain drugs.