Pluripotent Stem Cell-Derived Hepatocyte-like Cells: A Tool to Study Infectious Disease

Abstract

Purpose of Review: Liver disease is an important clinical and global problem and is the 16th leading cause of death worldwide and responsible for 1 million deaths worldwide each year. Infectious disease is a major cause of liver disease specifically and overall is even a greater cause of patient morbidity and mortality. Tools to study human liver disease and infectious disease have been lacking which has significantly hampered the study of liver disease generally and hepatotropic pathogens more specifically. Historically, hepatoma cell lines have been used for in vitro cell culture models to study infectious disease. Significant differences between human hepatoma cell lines and the human hepatocyte has hampered our understanding of hepatocyte pathogen infection and hepatocyte-–pathogen interactions. Recent Findings: Despite these limitations, great progress was made in the understanding of specific aspects of the life cycle of the canonical hepatocyte viral pathogen, Hepatitis C Virus. Over time various specific drugs targeting various proteins of the HCV virion or aspects of the HCV viral life cycle have been created that enable almost complete elimination of the virus in vitro and clinically. These drugs, direct-acting antivirals have enabled achieving sustained virologic response in over 90–95 percent of patients. Summary: Despite the development of direct-acting antivirals and the extreme success in achieving sustained virologic response, there has only been limited success elucidating host–pathogen interactions largely due to the poor nature of the hepatoma platform. Alternative approaches are needed. Pluripotent stem cells are renewable, can be derived from a single donor and can be efficiently and reproducibly differentiated towards many cell types including ectodermal-, endodermal-, and mesodermal-derived lineages. The development of pluripotent stem cell-derived hepatocyte-like cells (iHLCS) changes the paradigm as robust cells with the phenotype and function of hepatocytes can be readily created on demand with a variety of genetic background or alterations. iHLCs are readily used as models to study human drug metabolism, human liver disease, and human hepatotropic infectious disease. In this review, we discuss the biology of the HCV virus, the use of iHLCs as models to study human liver disease, and review the current work on using iHLCs to study HCV infection.