Elucidation of hepatitis virus infection / replication mechanism using genome-modified human pluripotent stem cells

• Project/Area Number: 26293178
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokai University
• Principal Investigator: KAMIYA Akihide 東海大学, 医学部, 准教授 (30321904)
• Co-Investigator(Renkei-kenkyūsha): KAKINUMA Sei 東京医科歯科大学, 医学部, 准教授 (30372444)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2017: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2015: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
• Keywords: ヒトiPS細胞 / 肝炎ウイルス / 肝再生 / 肝前駆細胞 / 再生医学 / ウイルス / 幹細胞 / ウィルス

Outline of Final Research Achievements

Chronic infection of hepatitis B virus (HBV, HCV) is a major cause of cirrhosis, liver cancer etc in Japan. However, it was difficult to analyze because of the species specificity of its infectivity. In this study, for the purpose of deriving hepatocytes from human iPS cells and constructing an HBV infection analysis system, 1) preparation of highly expressed human hepatocytes of HBV receptors, 2) genes responsible for high function of hepatocytes Screening, etc. were conducted. As a result, it has been found that HBV is efficiently infected / amplified in human iPS cell-derived hepatocytes overexpressing Ntcp, and that KLF 15 is important for enhancing hepatocyte function.

Research Products

• [Journal Article] Characteristics of hepatic progenitor cells during liver development and regeneration. (2017)
  • Author(s): Kamiya A, Chikada H.
  • Journal Title: Stem Cells in Clinical Applications “Liver, Lung and Heart Regeneration” (edited by Phuc Van Pham) Volume: 1 Pages: 3-13
  • DOI: 10.1007/978-3-319-46693-4_1
  • ISBN: 9783319466927, 9783319466934
• [Journal Article] Identification of a novel alpha-fetoprotein- expressing cell population induced by Jagged1/Notch2 signal in murine fibrotic liver. (2017)
  • Author(s): Yasuhiro Nakano, Sachie Nakao, Hideaki Sumiyoshi, Kenichiro Mikami, Yuri Tanno, Minako Sueoka, Daigo Kasahara, Hiroshi Kimura, Tadashi Moro, Akihide Kamiya, Katsuto Hozumi, Yutaka Inagaki
  • Journal Title: Hepatol Commun Volume: 印刷中 Issue: 3 Pages: 1-15
  • DOI: 10.1002/hep4.1026
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Human induced pluripotent stem cell-derived hepatic cell line as a new model for host interaction with hepatitis B virus. (2016)
  • Author(s): Kaneko S, Kakinuma S, Asahina Y, Kamiya A, Miyoshi M, Tsunoda T, Nitta S, Asano Y, Nagata H, Otani S, Kitahata F, Murakawa M, Itsui Y, Nakagawa M, Azuma S, Nakauchi H, Iwamoto M, Watashi K, Wakita T, Sugiyama M, Mizokami M, Shimotohno K, Watanabe M.
  • Journal Title: Sci Rep Volume: ６ Issue: 1 Pages: 29358-29358
  • DOI: 10.1038/srep29358
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Investigation of bi-potent differentiation of hepatoblasts using inducible diphtheria toxin receptor- transgenic mice. (2015)
  • Author(s): Yanagida A, Mizuno N, Yamazaki Y, Kato-Itoh M, Umino A, Sato H, Ito K, Yamaguchi T, Nakauchi H, Kamiya A.
  • Journal Title: Hepatol Res. Volume: Nov 19. Issue: 8 Pages: 816-828
  • DOI: 10.1111/hepr.12622
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The basic helix-loop-helix transcription factor, Mist1, induces maturation of mouse fetal hepatoblasts. (2015)
  • Author(s): Chikada H, Ito K, Yanagida A, Nakauchi H, Kamiya A
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 14989-14989
  • DOI: 10.1038/srep14989
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MEK-ERK activity regulates the proliferative activity of fetal hepatoblasts through accumulation of p16/19cdkn2a. (2015)
  • Author(s): Kamiya A, Ito K, Yanagida A, Chikada H, Iwama A, Nakauchi H
  • Journal Title: Stem Cells and Developments Volume: 24 Issue: 21 Pages: 2525-2535
  • DOI: 10.1089/scd.2015.0015
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Liver maturation deficiency in p57Kip2-/- mice occurs in a hepatocytic p57Kip2 expression-independent manner. (2015)
  • Author(s): agida A, Chikada H, Ito K, Umino A, Kato-Itoh M, Yamazaki Y, Sato H, Kobayashi T, Yamaguchi T, Nakayama KI, Nakauchi H, Kamiya A.
  • Journal Title: Dev Biol. Volume: 407(2) Issue: 2 Pages: 331-43
  • DOI: 10.1016/j.ydbio.2015.07.004
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A paracrine mechanism accelerating expansion of human induced pluripotent stem cell-derived hepatic progenitor-like cells (2015)
  • Author(s): Kota Tsuruya, Hiromi Chikada, Kinuyo Ida, Kazuya Anzai, Tatehiro Kagawa, Yutaka Inagaki, Tetsuya Mine, and Akihide Kamiya
  • Journal Title: Stem cells and Developments Volume: null Issue: 14 Pages: 1691-1702
  • DOI: 10.1089/scd.2014.0479
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A paracrine mechanism accelerating expansion of human iPS cell-derived hepatic progenitor-like cells. (2015)
  • Author(s): Tsuruya K, Chikada H, Ida K, Anzai K, Kagawa Y, Inagaki Y, Mine T, and Kamiya A
  • Journal Title: Stem Cell Dev. Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 肝前駆細胞の成熟化を誘導する転写調節機構 (2017)
  • Author(s): 紙谷聡英、安斎和也、鶴谷康太、近田裕美
  • Organizer: 第17回日本再生医療学会
• [Presentation] 肝前駆細胞由来胆管組織形成の分化制御メカニズム (2016)
  • Author(s): 紙谷聡英、安斎和也、近田裕美、峯徹哉
  • Organizer: 第15回日本再生医療学会
  • Place of Presentation: 大阪国際会議場・大阪
  • Year and Date: 2016-03-19
• [Presentation] ヒト多能性幹細胞由来肝前駆細胞の誘導と性状解析 (2015)
  • Author(s): 紙谷 聡英、鶴谷 康太、近田 裕美
  • Organizer: 第22回肝細胞研究会
  • Place of Presentation: 米子コンベンションセンター・鳥取
  • Year and Date: 2015-06-04