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.

iPSC-Derived Hepatocytes as a Platform for Disease Modeling and Drug Discovery

“…Historically, hepatoma cell lines have been used for in vitro cell culture models to study infectious disease, but these cells do not always accurately recapitulate the functioning of primary human hepatocytes making the study of hepatotropic infections such as Hepatitis C (HCV), which has a narrow host range, challenging (92). However, researchers found that hepatocytes derived from iPSCs provided an available source of cells with a consistent genetic background that were permissible to HCV infection and completion of the HCV life cycle (93, 94).…”

Stem cell models as an in vitro model for predictive toxicology

“…The necessity to generate data on the potential toxicity of at least 30,000 compounds, is expected to require up to 10 million animals [17]. In one study, iPSCs were derived from patients with α1antitrypsin (A1AT) deficiency [18], and through high-throughput screening, a compound that significantly reduced defective A1AT within the cytoplasm was identified [19]. As a result, iPSCs from diseased donors are being investigated for other conditions, including hypercholesterolaemia [20], glycogen storage disease [20–23], Gaucher's disease [24], hereditary tyrosinaemia [20], hereditary cholestasis [18] and defective mitochondrial respiratory chain complex disorder [23].…”

The Use of Human Pluripotent Stem Cells for Modeling Liver Development and Disease

“…This will be of particular use for enhancing the resolution of GWAS validation studies and in examining subtle phenotypes. It is also important to note that iPSC‐derived hepatocytes can be used to study infectious liver disease, such as hepatitis B and C viruses and the liver stages of the Plasmodium life cycle . In this context, iPSC hepatocytes could be particularly useful to probe the variation of host responses to such infections …”

“…It is also important to note that iPSC-derived hepatocytes can be used to study infectious liver disease, such as hepatitis B and C viruses and the liver stages of the Plasmodium life cycle. (70) In this context, iPSC hepatocytes could be particularly useful to probe the variation of host responses to such infections. (71) Taken together, our understanding of liver disease and development will benefit from continued efforts to generate stem cell-derived liver cells with reduced donor variability and greater maturity in more complex, but scalable, configurations.…”