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      Cell Culture Models for Hepatitis E Virus

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          Abstract

          Despite a growing awareness, hepatitis E virus (HEV) remains understudied and investigations have been historically hampered by the absence of efficient cell culture systems. As a result, the pathogenesis of HEV infection and basic steps of the HEV life cycle are poorly understood. Major efforts have recently been made through the development of HEV infectious clones and cellular systems that significantly advanced HEV research. Here, we summarize these systems, discussing their advantages and disadvantages for HEV studies. We further capitalize on the need for HEV-permissive polarized cell models to better recapitulate the entire HEV life cycle and transmission.

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          Most cited references105

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

          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.

            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.

              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
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                03 July 2019
                July 2019
                : 11
                : 7
                : 608
                Affiliations
                [1 ]Schaller Research Group at Department of Infectious Diseases and Virology, Heidelberg University Hospital, Cluster of Excellence CellNetworks, 69120 Heidelberg, Germany
                [2 ]Heidelberg Biosciences International Graduate School, Heidelberg University, 69120 Heidelberg, Germany
                Author notes
                [* ]Correspondence: VietLoan.DaoThi@ 123456med.uni-heidelberg.de ; Tel.: +49-6221-5635643
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-7423-5676
                https://orcid.org/0000-0003-2293-3592
                Article
                viruses-11-00608
                10.3390/v11070608
                6669563
                31277308
                07ae6b68-5368-48b6-9a49-88cd7554fbab
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 June 2019
                : 29 June 2019
                Categories
                Review

                Microbiology & Virology
                hepatitis e virus,cell culture systems,stem cells,hepatocyte polarization

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