AUTHOR=Yuan Lunzhi , Liu Xuan , Zhang Liang , Li Xiaoling , Zhang Yali , Wu Kun , Chen Yao , Cao Jiali , Hou Wangheng , Zhang Jun , Zhu Hua , Yuan Quan , Tang Qiyi , Cheng Tong , Xia Ningshao 

TITLE=A Chimeric Humanized Mouse Model by Engrafting the Human Induced Pluripotent Stem Cell-Derived Hepatocyte-Like Cell for the Chronic Hepatitis B Virus Infection

JOURNAL=Frontiers in Microbiology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2018.00908

DOI=10.3389/fmicb.2018.00908

ISSN=1664-302X

ABSTRACT=<p>Humanized mouse model generated by grafting primary human hepatocytes (PHHs) to immunodeficient mouse has contributed invaluably to understanding the pathogenesis of hepatitis B virus (HBV). However, the source of PHHs is limited, which necessitates the search for alternatives. Recently, hepatocyte-like cells (HLCs) generated from human induced pluripotent stem cells (hiPSCs) have been used for <italic>in vitro</italic> HBV infection. Herein, we developed a robust human liver chimeric animal model to study <italic>in vivo</italic> HBV infection by engrafting the hiPSC-HLCs to <italic>Fah<sup>-/-</sup>Rag2<sup>-/-</sup>IL-2Rγc<sup>-/-</sup></italic><italic>SCID</italic> (FRGS) mice. After being optimized by a small molecule, XMU-MP-1, the hiPSC-HLCs engrafted FRGS (hHLC-FRGS) mice displayed approximately 40% liver chimerism at week 6 after engraftment and maintained at this level for at least 14 weeks. Viremia and HBV infection markers include antigens, RNA, DNA, and covalently closed circular DNA were detectable in HBV infected hHLC-FRGS mice. Furthermore, hiPSC-HLCs and hHLC-FRGS mice were successfully used to evaluate different antivirals. Therefore, we established a humanized mouse model for not only investigating HBV pathogenesis but also testing the effects of the anti-HBV drugs.</p><p><bold>Highlights</bold>:</p><p>   (1) The implanted hiPSC-HLCs established a long-term chimerism in FRGS mice liver.</p><p>   (2) hHLC-FRGS mice are adequate to support chronic HBV infection with a full viral life cycle.</p><p>   (3) hiPSC-HLCs and hHLC-FRGS mice are useful tools for evaluation of antivirals against HBV infection <italic>in vitro</italic> and <italic>in vivo</italic>.</p><p><bold>Research in Context</bold> </p><p>To overcome the disadvantages of using primary human hepatocytes, we induced human pluripotent stem cells to hepatocyte-like cells (hiPSC-HLCs) that developed the capability to express important liver functional markers and critical host factors for HBV infection. The hiPSC-HLCs were permissive for the HBV infection and supported a full HBV replication. The hiPSC-HLCs were then engrafted to immunodeficient mouse to establish a chimeric liver mouse model, which was capable of supporting HBV infection <italic>in vivo</italic> and evaluating the effects of antiviral drugs. Our results shed light into improving the cellular and animal models for studying HBV and other hepatotropic viruses.</p>