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      Stem Cell–Derived Culture Models of Hepatitis E Virus Infection

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      Journal: Cold Spring Harbor Perspectives in Medicine
      Publisher: Cold Spring Harbor Laboratory

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          Abstract

          Similar to other hepatotropic viruses, hepatitis E virus (HEV) has been notoriously difficult to propagate in cell culture, limiting studies to unravel its biology. Recently, major advances have been made by passaging primary HEV isolates and selecting variants that replicate efficiently in carcinoma cells. These adaptations, however, can alter HEV biology. We have explored human embryonic or induced pluripotent stem cell (hESC/iPSC)-derived hepatocyte-like cells (HLCs) as an alternative to conventional hepatoma and hepatocyte cell culture systems for HEV studies. HLCs are permissive for nonadapted HEV isolate genotypes (gt)1–4 replication and can be readily genetically manipulated. HLCs, therefore, enable studies of pan-genotype HEV biology and will serve as a platform for testing anti-HEV treatments. Finally, we discuss how hepatocyte polarity is likely an important factor in the maturation and spread of infectious HEV particles.

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          Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

          Huan Yan, Guocai Zhong, Guangwei Xu … (2012)
          Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157–165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV. DOI: http://dx.doi.org/10.7554/eLife.00049.001
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            Organoids as an in vitro model of human development and disease.

            Aliya Fatehullah, Si Hui Tan, Nick Barker (2016)
            The in vitro organoid model is a major technological breakthrough that has already been established as an essential tool in many basic biology and clinical applications. This near-physiological 3D model facilitates an accurate study of a range of in vivo biological processes including tissue renewal, stem cell/niche functions and tissue responses to drugs, mutation or damage. In this Review, we discuss the current achievements, challenges and potential applications of this technique.
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              Microscale culture of human liver cells for drug development.

              Salman R. Khetani, Sangeeta N. Bhatia (2008)
              Tissue function depends on hierarchical structures extending from single cells ( approximately 10 microm) to functional subunits (100 microm-1 mm) that coordinate organ functions. Conventional cell culture disperses tissues into single cells while neglecting higher-order processes. The application of semiconductor-driven microtechnology in the biomedical arena now allows fabrication of microscale tissue subunits that may be functionally improved and have the advantages of miniaturization. Here we present a miniaturized, multiwell culture system for human liver cells with optimized microscale architecture that maintains phenotypic functions for several weeks. The need for such models is underscored by the high rate of pre-launch and post-market attrition of pharmaceuticals due to liver toxicity. We demonstrate utility through assessment of gene expression profiles, phase I/II metabolism, canalicular transport, secretion of liver-specific products and susceptibility to hepatotoxins. The combination of microtechnology and tissue engineering may enable development of integrated tissue models in the so-called 'human on a chip'.
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                Author and article information

                Journal
                Title: Cold Spring Harbor Perspectives in Medicine
                Abbreviated Title: Cold Spring Harb Perspect Med
                Publisher: Cold Spring Harbor Laboratory
                ISSN (Electronic): 2157-1422
                Publication date Created: March 01 2019
                Publication date Created: March 2019
                Publication date (Print): March 2019
                Publication date (Electronic): April 23 2018
                Volume: 9
                Issue: 3
                Page: a031799
                Article
                DOI: 10.1101/cshperspect.a031799
                PMC ID: 6396339
                PubMed ID: 29686039
                SO-VID: a9c27cdd-6777-489a-a4a4-c41741acc1bf
                Copyright © © 2018
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