Recent Advances for Enhancing Drug Metabolizing Functions of Hepatocyte-like Cells Derived from Human Pluripotent Stem Cells

Abstract

Hepatocyte-like cells (HLCs) derived from human pluripotent stem cells are a promising cell source for drug screening and toxicity tests. Thus, various hepatic differentiating protocols have been developed, leading to a hepatic differentiation efficiency of approximately 90%. However, HLC drug metabolizing ability remains very low compared to human primary hepatocytes. In order to overcome this problem, several alternative methods, such as, co-culture, three-dimensional (3D) culture, bioreactor, nanochip-based, etc., have been developed, but optimization to produce fully functional HLCs is ongoing. Recently, our group reported that repeated exposure of HLCs to xenobiotics can improve the expression of hepatic metabolizing enzymes such as cytochrome P450s (CYPs) and glutathione S-transferases (GSTs). These data suggest that we should develop strategies for differentiating cells into mature HLCs by more closely mimicking in vivo fetal and postnatal liver development. Here, we review the current development of alternative methods for enhancing the drug metabolizing functions of HLCs derived from human embryonic stem cells, human-induced pluripotent stem cells, and mesenchymal stem cells as used for drug screening and toxicity tests.