In vitro differentiation of pluripotent stem cells into hepatocyte like cells - Basic principles and current progress

Research in the field of hepatology is limited by the incomplete recapitulation of all major aspects of human hepatic metabolism in most established models. This restricts our ability to study the molecular mechanisms underlying hepatic diseases, and it leads to inadequate assessment of toxicology during drug development, resulting in tremendous unnecessary costs for the pharma industry. Animal models differ in their metabolism compared to the human system, while primary human cells dedifferentiate rapidly and are not suitable for long-term culture and studies. To overcome these obstacles, several protocols for in vitro differentiation of pluripotent stem cells into hepatocyte like cells (HLCs) have been established. These cells are currently used for modeling inherited and acquired diseases, and to test for drug efficacy and toxicity. Unfortunately, HLCs lack maturity and resemble rather fetal than adult hepatocytes. Novel 3D-based models may overcome these drawbacks in the future. In this review, we critically analyse the most common differentiation protocols and their evolution. In addition, we introduce recently developed techniques for 3D differentiation. Finally, we discuss drawbacks, challenges, and advantages of the distinct systems for routine toxicity tests, disease modeling and future cell replacement therapies.