Future Challenges in the Generation of Hepatocyte-Like Cells From Human Pluripotent Stem Cells

The purpose of this review is to provide an updated perspective on directing human pluripotent stem cells (hPSCs) to hepatocyte-like-cells (HLCs) and the associated challenges. Recent advances in the hepatocyte differentiation field have largely been focused on increasing the reproducibility and definition of culture systems to further their translation to a clinical setting. There have been advances using new extracellular matrices such as human laminins, and recent work using small molecules to drive the differentiation process has dramatically reduced the cost of producing HLCs with equivalent phenotypes to growth factor-derived cells. There are still several key aspects that remain unresolved, including the immature phenotype of hPSC-derived HLCs (a major hurdle for hPSC-derived progeny). Another key question is the zonal identity of the HLCs produced in vitro, which will have major implications in terms of disease modeling and drug metabolism. To date, there has been little investigation of this aspect of hepatic biology reported in the field.