Hepatocyte-like cells differentiated from human induced pluripotent stem cells (iHLCs) are permissive to hepatitis C virus (HCV) infection: HCV study gets personal

Abstract

Human pathogens impact patient health through a complex interplay with the host, but models to study the role of host genetics in this process are limited. Human induced pluripotent stem cells (iPSCs) offer the ability to produce host-specific differentiated cells and thus have the potential to transform the study of infectious disease; however, no iPSC models of infectious disease have been described. Here we report that hepatocyte-like cells derived from iPSCs support the entire life cycle of hepatitis C virus, including inflammatory responses to infection, enabling studies of how host genetics impact viral pathogenesis.Ó 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.HCV infection is a major health problem worldwide since at least 70% of infections persist and cause chronic hepatitis which may progress to liver cirrhosis and hepatocellular carcinoma [1]. The lack of robust cell culture and small animal models persists as stumbling blocks to HCV research. Fortunately, thanks to the development of cell culture systems that support HCV replication [2], the entire HCV life cycle is now accessible for investigation. However, despite its strong advantages, the HCVcc system cannot completely mimic the events that occur during a natural HCV infection in vivo. Recently, HepaRG progenitor cells were shown to be capable of differentiating into hepatocytes and biliary epithelial cells, depending on culture conditions [3]. These progenitors were used as a surrogate for primary human hepatocytes [4], and showed to be susceptible to in vitro infection with serum-derived HCV (genotype 3) and able to support long-term production of infectious lipoprotein-associated enveloped HCV particles [5]. Taking these findings a step further, the model described by Schwartz, Trehan et al. offers the possibility to study genetic defects that impact HCV infection of human iPS-derived hepatocyte-like cells (iHLCs) [6].The iHLC is an interesting and original cell system for HCV studies. It results from the efficient generation of highly differentiated hepatocyte-like cells from iPS cells that display key liver functions and can integrate into the hepatic parenchyma in vivo [7]. Inhibition of HNF4a in this system was shown to perturb hepatocyte differentiation once the endoderm was specified, mimicking previous findings generated from mouse knockout models, suggesting the usefulness of this model to study hepatocyte development in a human context [8]. The HLCs and iHLCs co-express alpha fetoprotein and albumin, as well as a repertoire of phase-1 and phase-2 drug metabolizing enzymes, which are known to be expressed in fetal but also adult hepatocytes. To date, studies using HLC were able to show their application in detoxification [9] when differentiated from human ES cells and modeling metabolic inborn genetic disease (for review, see [10]) when differentiated from human iPS cells. This is the first time that HLCs were described as a model to study host-pathogen interactions [6].Schwartz, ...

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

“…Another in vitro application will be for the study of hepatitis infection and disease. Recently it has been shown that both mouse and human iPS-derived hepatocytes are capable of HCV infection and replication (Aly et al 2011; Yoshida et al 2011; Si-Tayeb et al 2012). …”

Guidelines for the use of cell lines in biomedical research

“…In the case of hESCs the risk of contamination of the original donor tissue with the most serious blood-borne pathogens is very low ( Zou et al , 2004 ). However, when stem cell lines are differentiated to form tissue cell types they may provide a suitable culture substrate for the growth of pathogenic viruses such as HCV, HBV ( Si-Tayeb et al , 2012 ) and other pathogens depending on the cell types generated ( Bandi and Akkina, 2008 ). Thus, when planning experiments to provide a particular differentiated cell type, consideration should be given to the most likely contaminants that may arise in reagents, cells and any test samples that might replicate in the differentiated cell types.…”

The potential of induced pluripotent stem cell derived hepatocytes

“…Stem cell derived hepatocytes have also become invaluable for use in modelling infectious diseases such as hepatitis C virus (HCV) infection [93][94][95] and malaria in order to establish effective systems to investigate disease progression and assays for drug screening. Various groups [33,96] employed the use of hiPSC-HEPs in investigating HCV infection.…”