Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 7, 2021; 27(29): 4784-4801
Published online Aug 7, 2021. doi: 10.3748/wjg.v27.i29.4784
Hepatitis B virus infection modeling using multi-cellular organoids derived from human induced pluripotent stem cells
Di Cao, Jian-Yun Ge, Yun Wang, Tatsuya Oda, Yun-Wen Zheng
Di Cao, Yun Wang, Yun-Wen Zheng, Institute of Regenerative Medicine and Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang 212001, Jiangsu Province, China
Jian-Yun Ge, Tatsuya Oda, Yun-Wen Zheng, Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, Japan
Jian-Yun Ge, Yun-Wen Zheng, Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, and School of Biotechnology and Heath Sciences, Wuyi University, Jiangmen 529020, Guangdong Province, China
Yun-Wen Zheng, School of Medicine, Yokohama City University, Yokohama 234-0006, Kanagawa, Japan
Author contributions: Zheng YW conceptualized and designed this study, and conceived the writing; Cao D and Ge JY collected data and drafted the manuscript; Ge JY, Cao D, Wang Y and Zheng YW reviewed, discussed and revised the manuscript; all authors approved the final manuscript; Cao D and Ge JY contributed equally to this work; Zheng YW and Oda T are senior authors and co-correspondents of this work.
Supported by National Natural Science Foundation of China, No. 82070638 and No. 81770621; and JSPS KAKENHI, No. JP18H02866.
Conflict-of-interest statement: The authors declare no potential financial interests.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Yun-Wen Zheng, PhD, Associate Professor, Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba 305-8575, Ibaraki, Japan.
Received: March 9, 2021
Peer-review started: March 9, 2021
First decision: April 17, 2021
Revised: April 30, 2021
Accepted: July 15, 2021
Article in press: July 15, 2021
Published online: August 7, 2021

Chronic infection with hepatitis B virus (HBV) remains a global health concern despite the availability of vaccines. To date, the development of effective treatments has been severely hampered by the lack of reliable, reproducible, and scalable in vitro modeling systems that precisely recapitulate the virus life cycle and represent virus-host interactions. With the progressive understanding of liver organogenesis mechanisms, the development of human induced pluripotent stem cell (iPSC)-derived hepatic sources and stromal cellular compositions provides novel strategies for personalized modeling and treatment of liver disease. Further, advancements in three-dimensional culture of self-organized liver-like organoids considerably promote in vitro modeling of intact human liver tissue, in terms of both hepatic function and other physiological characteristics. Combined with our experiences in the investigation of HBV infections using liver organoids, we have summarized the advances in modeling reported thus far and discussed the limitations and ongoing challenges in the application of liver organoids, particularly those with multi-cellular components derived from human iPSCs. This review provides general guidelines for establishing clinical-grade iPSC-derived multi-cellular organoids in modeling personalized hepatitis virus infection and other liver diseases, as well as drug testing and transplantation therapy.

Keywords: Hepatitis B virus, Induced pluripotent stem cells, Liver organoid, Multi-cellular organoid, Modeling, Transplantable

Core Tip: The development of an effective treatment for hepatitis B virus relies on reliable and reproducible in vitro modeling systems. Recently, three-dimensional multi-cellular organoid systems have attracted considerable attention owing to their superior susceptibility and capability to precisely recapitulate the virus life cycle. Recent advances in organoid-generating strategies, particularly those derived from human induced pluripotent stem cells, together with future improvements in genetic modification and scalability, will undoubtedly promote personalized disease modeling and drug development.