EBioMedicine. 2018 Aug 14. pii: S2352-3964(18)30300-1. doi: 10.1016/j.ebiom.2018.08.014. [Epub ahead of print]
Recapitulation of hepatitis B virus-host interactions in liver organoids from human induced pluripotent stem cells.
Nie YZ1, Zheng YW2, Miyakawa K3, Murata S1, Zhang RR1, Sekine K1, Ueno Y1, Takebe T1, Wakita T4, Ryo A3, Taniguchi H5.
Author information
1
Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
2
Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Department of Advanced Gastroenterological Surgical Science and Technology, University of Tsukuba, Tsukuba-shi, Ibaraki 305-8575, Japan; Research Center of Stem Cells and Regenerative Medicine, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China,. Electronic address: [email protected].
3
Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.
4
Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, 162-8640 Tokyo, Japan.
5
Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan. Electronic address: [email protected].
Abstract
Therapies against hepatitis B virus (HBV) have improved in recent decades; however, the development of individualized treatments has been limited by the lack of individualized infection models. In this study, we used human induced pluripotent stem cell (hiPSC) to generate a functional liver organoid (LO) that inherited the genetic background of the donor, and evaluated its application in modeling HBV infection and exploring virus-host interactions. To establish a functional hiPSC-LO, we cultured hiPSC-derived endodermal, mesenchymal, and endothelial cells with a chemically defined medium in a three-dimensional microwell culture system. Based on cell-cell interactions, these cells could organize themselves and gradually differentiate into a functional organoid, which exhibited stronger hepatic functions than hiPSC derived hepatic like cell (HLC). Moreover, the functional LO demonstrated more susceptibility to HBV infection than hiPSC-HLC, and could maintain HBV propagation and produce infectious virus for a prolonged duration. Furthermore, we found that virus infection could cause hepatic dysfunction of hiPSC-LOs, with down-regulation of hepatic gene expression, induced release of early acute liver failure markers, and altered hepatic ultrastructure. Therefore, our study demonstrated that HBV infection in hiPSC-LOs could recapitulate virus life cycle and virus induced hepatic dysfunction, suggesting that hiPSC-LOs may provide a promising individualized infection model for the development of individualized treatment for hepatitis.
KEYWORDS:
Hepatitis B virus; Liver organoid; Virus-host interactions; hiPSC