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

Abstract

Clinical treatment for chronic liver failure using human embryonic stem cell (hESC) and human-induced pluripotent stem cell (hiPSC)-derived hepatocyte-like cells (HLCs) is considered a promising alternative method to organ transplantation. In addition to their use for treatment in liver failure, stem cell-derived HLCs have been considered for in vitro drug screening and toxicology researches [1]. Therefore, HLCs directly induced from hESCs have been intensively studied, resulting in a significant improvement in the efficiency of hepatic differentiation using human pluripotent stem cells. Albumin-positive HLCs can now be produced at the end of in vitro hepatic differentiation at levels up to 90% [2,3]. However, in spite of efforts to induce further maturation of HLCs derived from human pluripotent stem cells, the phenotype of most HLCs is more similar to fetal hepatocytes rather than fully mature hepatocytes. Critical inducing mature hepatocyte functions, such as phase I and II enzyme activity, tend to be significantly reduced in 2D-cultured HLCs (approximately <1% of human primary hepatocytes) [4,5]. Furthermore, under in vitro culture conditions, hepatobiliary transporter expression rapidly decreases [6], and most HLCs are spontaneously differentiate into various cell lineages, regardless of the differentiation protocol. Thus, at the final stage of hepatic differentiation, purification is needed to obtain highly homogenous HLCs. These key differences between HLCs and human primary hepatocytes result in limited use of HLCs as Hanyang Med Rev 2015;35:196-206 http://dx.doi.org/10.7599/hmr.2015.35.4.196