Human pluripotent stem cells for modeling toxicity

Abstract

The development of xenobiotics, driven by the demand for therapeutic, domestic and industrial uses continues to grow. However, along with this increasing demand is the risk of xenobiotic-induced toxicity. Currently, safety screening of xenobiotics uses a plethora of animal and in vitro model systems which have over the decades proven useful during compound development and for application in mechanistic studies of xenobiotic-induced toxicity. However, these assessments have proven to be animal-intensive and costly. More importantly, the prevalence of xenobiotic-induced toxicity is still significantly high, causing patient morbidity and mortality, and a costly impediment during drug development. This suggests that the current models for drug safety screening are not reliable in toxicity prediction, and the results not easily translatable to the clinic due to insensitive assays that do not recapitulate fully the complex phenotype of a functional cell type in vivo. Recent advances in the field of stem cell research have potentially allowed for a readily available source of metabolically competent cells for toxicity studies, derived using human pluripotent stem cells harnessed from embryos or reprogrammed from mature somatic cells. Pluripotent stem cell-derived cell types also allow for potential disease modeling in vitro for the purposes of drug toxicology and safety pharmacology, making this model possibly more predictive of drug toxicity compared with existing models. This article will review the advances and challenges of using human pluripotent stem cells for modeling metabolism and toxicity, and offer some perspectives as to where its future may lie.