Recapitulation of hepatitis B virus–host interactions in liver organoids from human induced pluripotent stem cells

• Published in: EBioMedicine Vol. 35; pp. 114 - 123
• Main Authors: Nie, Yun-Zhong, Zheng, Yun-Wen, Miyakawa, Kei, Murata, Soichiro, Zhang, Ran-Ran, Sekine, Keisuke, Ueno, Yasuharu, Takebe, Takanori, Wakita, Takaji, Ryo, Akihide, Taniguchi, Hideki
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2018; Elsevier
• Subjects: Advanced Basic Science; Cell Line; Hepatitis B - pathology; Hepatitis B - virology; Hepatitis B virus; Hepatitis B virus - physiology; hiPSC; Host-Pathogen Interactions; Humans; Induced Pluripotent Stem Cells - ultrastructure; Induced Pluripotent Stem Cells - virology; Internal Medicine; Liver - pathology; Liver - physiopathology; Liver - virology; Liver organoid; Organoids - ultrastructure; Organoids - virology; Research paper; Virus-host interactions; Liver organoid; Hepatitis B virus; hiPSC; Virus-host interactions
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2018.08.014

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.