title: Human induced pluripotent stem cell-derived hepatic cell lines as a new model for host interaction with hepatitis B virus.
abstract: Hepatitis B virus (HBV) is not eradicated by current antiviral therapies due to persistence of HBV covalently closed circular DNA (cccDNA) in host cells, and thus development of novel culture models for productive HBV infection is urgently needed, which will allow the study of HBV cccDNA eradication. To meet this need, we developed culture models of HBV infection using human induced pluripotent stem cell-derived hepatocyte lineages, including immature proliferating hepatic progenitor-like cell lines (iPS-HPCs) and differentiated hepatocyte-like cells (iPS-Heps). These cells were susceptible to HBV infection, produced HBV particles, and maintained innate immune responses. The infection efficiency of HBV in iPS-HPCs predominantly depended on the expression levels of sodium taurocholate cotransporting polypeptide (NTCP), and was low relative to iPS-Heps: however, long-term culture of iPS-Heps was difficult. To provide a model for HBV persistence, iPS-HPCs overexpressing NTCP were established. The long-term persistence of HBV cccDNA was detected in iPS-HPCs overexpressing NTCP, and depended on the inhibition of the Janus-kinase signaling pathway. In conclusion, this study provides evidence that iPS-derived hepatic cell lines can be utilized for novel HBV culture models with genetic variation to investigate the interactions between HBV and host cells and the development of anti-HBV strategies.
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.|Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Kakinuma
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.|Department for Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Asahina
authors.affiliation: Institute of Innovative Science and Technology, Tokai University, Isehara, Japan.
authors.forename: Akihide
authors.initials: A
authors.lastname: Kamiya
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Miyoshi
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Nitta
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Asano
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagata
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Otani
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Fukiko
authors.initials: F
authors.lastname: Kawai-Kitahata
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Murakawa
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Itsui
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Seishin
authors.initials: S
authors.lastname: Azuma
authors.affiliation: Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Nishitsuji
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Saneyuki
authors.initials: S
authors.lastname: Ujino
authors.affiliation: Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
authors.forename: Kunitada
authors.initials: K
authors.lastname: Shimotohno
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Watashi
authors.affiliation: Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D004270:DNA, Circular / Q000235:genetics* / Q000276:immunology; D004279:DNA, Viral / Q000235:genetics / Q000276:immunology; D056945:Hep G2 Cells; D006509:Hepatitis B / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D006515:Hepatitis B virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014779:Virus Replication
chemical_list: D004270:DNA, Circular; D004279:DNA, Viral; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C071908:sodium-bile acid cotransporter