Human iPS-derived hepatocyte-like progenitor cells susceptible for hepatitis B virus infection

• Project/Area Number: 25670366
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: ASAHINA Yasuhiro 東京医科歯科大学, 医歯(薬)学総合研究科, 寄附講座教授 (00422692)
• Co-Investigator(Kenkyū-buntansha): KAKINUMA Sei 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (30372444) ; NAKAGAWA Mina 東京医科歯科大学, 医歯学融合教育センター, 准教授 (30401342)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ＨＢＶ / iPS細胞 / 肝幹・前駆細胞 / HBV / cccDNA / 幹細胞分化

Outline of Final Research Achievements

It is unclear the mechanism responsible for persistence of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in mature hepatocyte, which constantly turn over in steady state of the liver. In the present study, we established culture system of human induced pluripotent stem (iPS) cell -derived hepatocyte-like progenitor cells. Using this culture system, we investigated infection of HBV, and demonstrated that HBV infected iPS-derived hepatocyte-like progenitor cells. Hence, it is possible HBV infection in hepatic progenitor cell may be one of the reasons for persistence of HBV in steady state of the liver. Moreover, the establishment of human iPS cell technology has led to innovative iPS-based models for drug discovery. Our data suggested iPS-Hep cells, as a promising new tool for HBV research, will facilitate our understanding of the biology of HBV and the development of anti-HBV drugs.

Research Products

• [Journal Article] Impaired induction of IL28B and expression of IFNλ4 associated with non-response to interferon-based therapy in chronic hepatitis C. (2015)
  • Author(s): Murakawa M, Asahina Y, Nakagawa M, Sakamoto N, Nitta S, Kusano-Kitazume A, Watanabe T, Kawai-Kitahata F, Otani S, Taniguchi M, Goto F, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M
  • Journal Title: J Gastroenterol Hepatol Volume: 印刷中 Issue: 6 Pages: 1075-84
  • DOI: 10.1111/jgh.12902
  • Peer Reviewed / Open Access
• [Journal Article] Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions. (2015)
  • Author(s): Suda G, Yamamoto Y, Nagasaka A, Furuya K, Kudo M, Chuganji Y, Tsukuda Y, Tsunematsu S, Sato F, Terasita K, Nakai M, Horimoto H, Sho T, Natsuizaka M, Ogawa K, Ohnishi S, Chuma M, Fujita Y, Abe R, Taniguchi M, Nakagawa M, Asahina Y, Sakamoto N
  • Journal Title: Hepatol Res Volume: 印刷中 Issue: 8 Pages: 837-45
  • DOI: 10.1111/hepr.12421
  • NAID: 120005820706
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hepatocellular carcinoma risk assessment using gadoxetic acid-enhanced hepatocyte phase magnetic resonance imaging. (2015)
  • Author(s): Komatsu N, Motosugi U, Maekawa S, Shindo K, Sakamoto M, Sato M, Tatsumi A, Miura M, Amemiya F, Nakayama Y, Inoue T, Fukasawa M, Uetake T, Ohtaka M, Sato T, Asahina Y, Kurosaki M, Izumi N, Ichikawa T, Araki T, Enomoto N.
  • Journal Title: Hepatol Res Volume: - Issue: 13 Pages: 1339-1346
  • DOI: 10.1111/hepr.12309
  • Peer Reviewed
• [Journal Article] Risk factors for exceeding the Milan criteria after successful radiofrequency ablation in patients with early stage hepatocellular carcinoma. (2014)
  • Author(s): Tsuchiya K, Asahina Y, Tamaki N, Yasui Y, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Kurosaki M, Enomoto N, Izumi N.
  • Journal Title: Liver Transpl Volume: 20 Pages: 291-297
  • Peer Reviewed
• [Journal Article] Reduced organic anion transporter expression is a risk factor for hepatocellular carcinoma in chronic hepatitis C patients. (2014)
  • Author(s): Yasui Y, Kudo A, Kurosaki M, Matsuda S, Muraoka M, Tamaki N, Suzuki S, Hosokawa T, Ueda K, Matsunaga K, Nakanishi H, Tsuchiya K, Itakura J, Takahashi Y, Tanaka S, Asahina Y, Enomoto N, Arii S, Izumi N.
  • Journal Title: Oncology Volume: 86(1) Issue: 1 Pages: 53-62
  • DOI: 10.1159/000356643
  • Peer Reviewed
• [Journal Article] New susceptibility and resistance HLA-DP alleles to HBV-related diseases identified by a trans-ethnic association study in Asia. (2014)
  • Author(s): Nishida N, Sawai H, Kashiwase K, Minami M, Sugiyama M, Seto WK, Yuen MF, Posuwan N, Poovorawan Y, Ahn SH, Han KH, Matsuura K, Tanaka Y, Kurosaki M, Asahina Y, Izumi N, Kang JK, （省略）, Tokunaga K, and Mizokami M
  • Journal Title: PLoS One Volume: 9 Issue: 2 Pages: e86449-e86449
  • DOI: 10.1371/journal.pone.0086449
  • Peer Reviewed / Open Access
• [Journal Article] Prospective comparison of real-time tissue elastography and serum fibrosis markers for the estimation of liver fibrosis in chronic hepatitis C patients. (2014)
  • Author(s): Tamaki N, Kurosaki M, Matsuda S, Nakata T, Muraoka M, Suzuki Y, Yasui Y, Suzuki S, Hosokawa T, Nishimura T, Ueda K, Tsuchiya K, Nakanishi H, Itakura J, Takahashi Y, Matsunaga K, Taki K, Asahina Y, Izumi N.
  • Journal Title: Hepatol Res Volume: 44 Issue: 7 Pages: 720-727
  • DOI: 10.1111/hepr.12179
  • Peer Reviewed
• [Journal Article] JSH guidelines for the management of hepatitis B virus infection. (2014)
  • Author(s): Asahina Y, HayashinN, Hiramatsu N, Izumi N, Koike K, Kumada H, Kurosaki M, Oketani M, Suzuki F, Takikawa H, Tanaka A, Tanaka E, Tanaka Y, Tsubouchi H, Yotsuyanagi H.
  • Journal Title: Hepatol Res Volume: 44 Issue: S1 Pages: 1-58
  • DOI: 10.1111/hepr.12269
  • Peer Reviewed
• [Journal Article] JSH guidelines for the management of hepatitis C virus infection: a 2014 update for genotype 1. (2014)
  • Author(s): Asahina Y, HayashinN, Hiramatsu N, Izumi N, Koike K, Kumada H, Kurosaki M, Oketani M, Suzuki F, Takikawa H, Tanaka A, Tanaka E, Tanaka Y, Tsubouchi H, Yotsuyanagi H.
  • Journal Title: Hepatol Res Volume: 44 Issue: S1 Pages: 59-70
  • DOI: 10.1111/hepr.12272
  • Peer Reviewed
• [Journal Article] Changes in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma. (2013)
  • Author(s): Tsuchiya K, Asahina Y, Matsuda S, Muraoka M, Nakata T, Suzuki Y, Tamaki N, Yasui Y, Suzuki S, Hosokawa T, Nishimura T, Ueda K, Kuzuya T, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Izumi N.
  • Journal Title: Cancer. Volume: 15;120(2) Issue: 2 Pages: 229-237
  • DOI: 10.1002/cncr.28384
  • Peer Reviewed
• [Journal Article] Impaired brain activity in cirrhotic patients with minimal hepatic encephalopathy: evaluation by near infrared spectroscopy. (2013)
  • Author(s): Nakanishi H,Asahina Y, Izumi N et al
  • Journal Title: Hepatol Res Volume: in press Issue: 3 Pages: 319-326
  • DOI: 10.1111/hepr.12127
  • Peer Reviewed
• [Journal Article] α-fetoprotein levels afterinterferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C (2013)
  • Author(s): Asahina Y, Tsuchiya K, Nishimura T, Muraoka M, Suzuki Y, Tamaki N, Yasui Y, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Nakagawa M, Kakinuma S, Watanabe M,Izumi N
  • Journal Title: Hepatology Volume: (in press) Issue: 4 Pages: 1253-1262
  • DOI: 10.1002/hep.26442
  • Peer Reviewed
• [Journal Article] Guidelines for the Management of Hepatitis C Virus Infection. (2013)
  • Author(s): Asahina Y, Hayashi N, Izumi N, Koike K, Kumada H, Oketani M, Suzuki F, Takikawa H, Tanaka A, Tsubouchi H, Yotsuyanagi H: editors of the Drafting Committee for Hepatitis Management Guidelines.
  • Journal Title: Hepatol Res Volume: 43 Issue: 1 Pages: 1-34
  • DOI: 10.1111/hepr.12020
  • NAID: 130003384472
  • Peer Reviewed
• [Journal Article] Inhibition of hepatocellular carcinoma by PegIFNα2a in patients with chronic hepatitis C: a nationwide multi-center cooperative study. (2013)
  • Author(s): Izumi N, Asahina Y, Kumada H et al
  • Journal Title: J Gastroenterol Volume: 48 Issue: 3 Pages: 382-390
  • DOI: 10.1007/s00535-012-0641-9
  • Peer Reviewed
• [Journal Article] Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type-I interferon-dependent innate immunity (2013)
  • Author(s): Nitta S, Sakamoto N, Nakagawa M, Kakinuma S, Mishima K, Kusano-kitazume A, Kiyohashi K, Murakawa M, Nishimura-Sakurai Y, Azuma S, Tasaka-Fujita M, asahina Y, Yoneyama M, Fujita T, Watanabe M
  • Journal Title: Hepatology Volume: 57 Issue: 1 Pages: 46-58
  • DOI: 10.1002/hep.26017
  • Peer Reviewed
• [Journal Article] Wnt5a Signaling Mediates Biliary Differentiation of Fetal Hepatic Stem/Progenitor Cells (2013)
  • Author(s): Kakinuma S, Kiyohashi K, Kamiya A, Sakamoto N, Nitta S, Yamanaka H, YoshinoK, Fujiki J, Murakawa M, Kusano-Kitazume A, Shimizu H, Okamoto R, Azuma S, Nakagawa M, Asahina Y, Tanimizu N, Kikuchi A, Nakauchi H, and *WatanabeM
  • Journal Title: Hepatology Volume: (in press) Issue: 6 Pages: 2502-2513
  • DOI: 10.1002/hep.26293
  • Peer Reviewed
• [Journal Article] Clinical Characteristics of Patients who Developed Hepatocellular Carcinoma after Hepatitis C Virus Eradication with Interferon Therapy: Current Status in Japan (2013)
  • Author(s): Sato A, SataM, Ikeda K, Kumada T, Izumi N, Asahina Y, Osaki Y, Chayama K, Kaneko S, Sakai A, Onji M, Hiasa Y, Omura T, Ozeki I, Yokosuka O, Shiina S, Itsubo M, Nishiguchi S, Hirano K, Ide T, Sakisaka S, Yamasaki T, Hidaka I, Tanaka M, Kim SR, Ichida T.
  • Journal Title: Internal Medicine Volume: 52 Issue: 24 Pages: 2701-2706
  • DOI: 10.2169/internalmedicine.52.1180
  • NAID: 130003383756
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Presentation] Gene Alterations in TERT promoter, CTNNB1, and TP53 are closely associated with development and prognosis of hepatocellular carcinoma: comprehensive analyses by next generation sequencing technology. (2015)
  • Author(s): Asahina Y, Kawai-Kitahata F, Kaneko S, Nagata H, Goto F, Otani S, Taniguchi M, Murakawa M, Nitta S, Watanabe T, Tasaka-Fujita M, Itsui Y, Nakagawa M, Kakinuma S, Tanaka S, Tanabe M, Enomoto N, Watanabe M.
  • Organizer: The 50th annual meeting of the European association for the study of the liver (EASL The International Liver Congress 2015)
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2015-04-23
• [Presentation] Gene alterations in β-catenin and p53/ cell cycle control pathway are closely associated with development and prognosis of hepatocellular carcinoma: Comprehensive analyses by next generation sequencing technology. (2014)
  • Author(s): Kawai-Kitahata F, Asahina Y, Kaneko S, Nagata H, Goto F, Otani S, Taniguchi M, Murakawa M, Nitta S, Watanabe T, Tasaka-Fujita M, Itsui Y, Nakagawa M, Kakinuma S, Enomoto N, Watanabe M.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Matrix Metalloproteinase-14 regulates the maturation of fetal hepatic stem/progenitor cells in mice. (2014)
  • Author(s): Otani S, Kakinuma S, Kamiya A, Goto F, Kaneko S, Azuma S, Asahina Y, Watanabe M.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Impact of host and therapeutic factors and resistant associated variants on response to interferon based- direct acting antiviral treatment in difficult-to-treat chronic hepatitis C patients. (2014)
  • Author(s): Nakagawa M, Asahina Y, Taniguchi M, Watanabe T, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Watanabe M.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Expression of IFN/.4 in liver and PBMC is closely associated with higher basal expression of ISGs and impaired induction of IL28B by interferon treatment in chronic hepatitis C non-responder patients. (2014)
  • Author(s): Murakawa M, Asahina Y, Nakagawa M, Sakamoto N, Nitta S, Kawai-Kitahata F, Taniguchi M, Watanabe T, Itsui Y, Kakinuma S, Watanabe M.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Emergence or selection of resistant associated variant immediately after initiation of the therapy is predictive for failure of direct acting antiviral therapy: ultra-deep sequencing analyses for serial time points. (2014)
  • Author(s): Watanabe T, Asahina Y, Nakagawa M, Kakinuma S, YItsui Y, Taniguchi T, Murakawa M, Nagata H, Miura M, Maekawa S, Enomoto E, Watanabe M.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Clinical outcomes in patients who develop hepatocellular carcinoma after hepatitis C viral eradication by antiviral therapy. (2014)
  • Author(s): Tsuchiya K, Yasui Y, Tamaki N, Suzuki S, Hosokawa T, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Asahina Y, Izumi N.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Associations of HLA-DPB1 with CHB infection and HBV related HCC in Asia. (2014)
  • Author(s): Nishida N, Sawai H, Asahina Y, Mizokami M, et al.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Impaired IL28B gene induction and expression of IFNλ4 influenced by the polymorphisms near IL28B gene are closely associated with a non-response to interferon in chronic hepatitis C patients. (2014)
  • Author(s): Asahina Y, Murakawa M, NittaS, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Watanabe M.
  • Organizer: The 49th annual meeting of the European association for the study of the liver (EASL The International Liver Congress 2014)
  • Place of Presentation: London, UK
  • Year and Date: 2014-04-08 – 2014-04-14
• [Presentation] Gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid magnetic resonance imaging and contrast enhanced ultrasonography with sonazoid as part of therapeutic strategies for small nonhypervascular hepatic nodular lesions. (2014)
  • Author(s): Tsuchiya K, Yasui Y, Takada N, Nakakuki S, Matsuda S, Kaneko S, Muraoka M, Yamashita N, Hattori N, Tamaki N, Osaki S, Suzuki T, Hosokawa K, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Asahina Y, Izumi N.
  • Organizer: The 49th annual meeting of the European association for the study of the liver (EASL The International Liver Congress 2014)
  • Place of Presentation: London, UK
  • Year and Date: 2014-04-08 – 2014-04-14
• [Presentation] Serum interleukin-6 levels during treatment correlate with resistance to telaprevir-based triple therapy in chronic hepatitis C (2013)
  • Author(s): Asahina Y, Nakagawa M, Taniguchi M, Kawai F, Fujiki J, Otani T, Yamanaka H, Murakawa M, Nitta S, Kitazume A, Watanabe T, Sakurai Y, Azuma S, Kakinuma S, Watanabe M
  • Organizer: The 48th annual meeting of the European association for the study of the liver (EASL The International Liver Congress 2013)
  • Place of Presentation: Amusterdam(Netherlands)
• [Presentation] Substitution of amino acid 70/91 in the hepatitis C virus core region affects infectious virus production and cell surface expression of MHC class I. (2013)
  • Author(s): Tasaka-Fujita M, Sugiyama N, Kang W, Murayama A, Asahina Y, Sakamoto N, Wakita T, Shin EC, Kato T
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2013)
  • Place of Presentation: Washington DC(USA)
• [Presentation] Impaired IL28B gene induction and expression of IFNλ4 are closely associated with a non-response to interferon-based therapy in chronic hepatitis C patients. (2013)
  • Author(s): Asahina Y, Murakawa M, NittaS, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Watanabe M
  • Organizer: The 64th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2013)
  • Place of Presentation: Washington DC(USA)