Establishment of human liver chimeric mice with normal immune system for hepatitis viral infection

• Project/Area Number: 23689040
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Tokai University
• Principal Investigator: KAMIYA Akihide 東海大学, 創造科学技術研究機構, 准教授 (30321904)
• Co-Investigator(Renkei-kenkyūsha): KAKINUMA Sei 東京医科歯科大学, 分子肝炎制御学講座, 特任講師 (30372444)
• Project Period (FY): 2011-11-18 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2013: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2012: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 肝炎ウイルス / 肝幹細胞 / 多能性幹細胞 / iPS細胞 / 肝前駆細胞 / 肝細胞生物学 / 肝幹・前駆細胞

Research Abstract

Viral hepatitis is a very severe liver disease. Studies for therapies of this disease are difficult because Hepatitis viruses cannot infect to normal experimental animals such as mouse and rat. Thus, we have a plan to establish a new mouse model for the studies of viral hepatitis.
(1) We established a new culture method for the purification and expansion of hepatic progenitor cells derived from human pluripotent cells. These cells are candidate of donor cells into human liver chimera mice.
(2) We tried to transplant primary hepatic progenitor cells derived into neonatal mice. Small numbers of donor cells were detected in the recipient liver and lung.

Research Products

• [Journal Article] Mesenchymal progenitor cells in mouse fetal liver regulate differentiation and proliferation of hepatoblasts (2014)
  • Author(s): Ito Keiichi, Yanagida Ayaka, Okada Ken, Yamazaki Yuji, Nakauchi Hiromitsu, Kamiya Akihide
  • Journal Title: Liver international Volume: (印刷中) Issue: 9 Pages: 1378-1390
  • DOI: 10.1111/liv.12387
  • Peer Reviewed
• [Journal Article] Mesenchymal progenitor cells in mouse fetal liver regulate differentiation and proliferation of hepatoblasts (2013)
  • Author(s): Ito K, Yanagida A, Okada K, Yamazaki Y, Nakauchi H, Kamiya A
  • Journal Title: Liver Int Volume: (in press)
  • Peer Reviewed
• [Journal Article] An in vitro expansion system for generation of human iPS cell-derived hepatic progenitor-like cells exhibiting a bipotent differentiation potential (2013)
  • Author(s): Yanagida A, Ito K, Chikada H, Nakauchi H, Kamiya A
  • Journal Title: PLoS One Volume: 8
  • Peer Reviewed
• [Journal Article] SALL4, a stem cell biomarker in liver cancers (2013)
  • Author(s): Oikawa T, Kamiya A, Zeniya M, Chikada H, Hyuck AD, Yamazaki Y, Wauthier E, Tajiri H, Miller LD, Wang XW, Reid LM, Nakauchi H
  • Journal Title: Hepatology Volume: 57 Pages: 1469-83
  • Peer Reviewed
• [Journal Article] An in vitro expansion system for generation of human iPS cell-derived hepatic progenitor-like cells exhibiting a bipotent differentiation potential. (2013)
  • Author(s): Yanagida A, Ito K, Chikada H, Nakauchi H, Kamiya A.
  • Journal Title: PLoS One. Volume: 8 Issue: 7 Pages: e67541-e67541
  • DOI: 10.1371/journal.pone.0067541
  • 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] Prospective Isolation and Characterization of Bipotent Progenitor Cells in Early Mouse Liver Development (2012)
  • Author(s): Okada K, Kamiya A, Ito K, Yanagida A, Ito H, Kondou H, Nishina H, Nakauchi H
  • Journal Title: Stem Cells Dev Volume: 21(7) Pages: 1124-33
  • Peer Reviewed
• [Journal Article] In vitro expansion and functional recovery of mature hepatocytes from mouse adult livers (2012)
  • Author(s): Ito H, Kamiya A, Ito K, Yanagida A, Okada K, Nakauchi H
  • Journal Title: Liver Int Volume: 32(4) Pages: 592-601
  • Peer Reviewed
• [Journal Article] Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers. (2012)
  • Author(s): Oikawa T, Kamiya A*, Zeniya M, Chikada H, Hyuck AD, Yamazaki Y, Wauthier E, Tajiri H, Miller LD, Wang XW, Reid LM*, Nakauchi H*.
  • Journal Title: Hepatology Volume: in press Issue: 4 Pages: 1469-83
  • DOI: 10.1002/hep.26159
  • Peer Reviewed
• [Journal Article] Development of an All-in-One Inducible Lentiviral Vector for Gene Specific Analysis of Reprogramming. (2012)
  • Author(s): Yamaguchi T, Hamanaka S, Kamiya A, Okabe M, Kawarai M, Wakiyama Y, Umino A, Hayama T, Sato H, Lee YS, Kato-Itoh M, Masaki H, Kobayashi T, Yamazaki S, Nakauchi H.
  • Journal Title: PLoS One. Volume: 7 Issue: 7 Pages: e41007-e41007
  • DOI: 10.1371/journal.pone.0041007
  • Peer Reviewed
• [Journal Article] Highly efficient generation of definitive endoderm lineage from human induced pluripotent stem cells (2012)
  • Author(s): Sekine K
  • Journal Title: Transplant Proc Volume: 44(4) Issue: 4 Pages: 1127-1129
  • DOI: 10.1016/j.transproceed.2012.03.001
  • Peer Reviewed
• [Journal Article] In vitro expansion and functional recovery of mature hepatocytes from mouse adult liver (2011)
  • Author(s): Ito H, Kamiya A, Ito K, Yanagida A, Okada K, Nakauchi H
  • Journal Title: Liver Int Volume: 32 Issue: 4 Pages: 592-601
  • DOI: 10.1111/j.1478-3231.2011.02741.x
  • Peer Reviewed
• [Journal Article] Prospective isolation and characterization of bi-potent progenitor cells in early mouse liver development (2011)
  • Author(s): Okada K, Kamiya A, Ito K, Yanagida A, Ito H, Kondou H, Nishina H, Nakauchi H
  • Journal Title: Cells Dev Volume: (Epub ahead of print) Issue: 7 Pages: 1124-33
  • DOI: 10.1089/scd.2011.0229
  • Peer Reviewed
• [Journal Article] Cholestatic liver fibrosis and toxin-induced fibrosis are exacerbated in matrix metalloproteinase-2 deficient mice (2011)
  • Author(s): Onozuka I, Sakamoto N, Nakagawa M, Watanabe M, et al.
  • Journal Title: Biochem Biophys Res Commun Volume: 406 Issue: 1 Pages: 134-140
  • DOI: 10.1016/j.bbrc.2011.02.012
  • Peer Reviewed
• [Presentation] 肝臓における薬物代謝の性差を制御する分子メカニズム (2014)
  • Author(s): 近田裕美、坂本明美、徳久剛史、紙谷聡英
  • Organizer: 第13回日本再生医療学会
  • Place of Presentation: 京都国際会館
• [Presentation] ヒト多能性幹細胞からのin vitro胆管組織誘導系の構築 (2014)
  • Author(s): 紙谷聡英、近田裕美、鶴谷康太、柳田絢加、中内啓光
  • Organizer: 第13回日本再生医療学会
  • Place of Presentation: 京都国際会館
• [Presentation] HLH型転写因子による胎生肝幹・前駆細胞の分化誘導 (2013)
  • Author(s): 近田裕美、紙谷聡英
  • Organizer: 第12回日本再生医療学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2013-03-23
• [Presentation] In vitro generation and expansion of bi-potent hepatic progenitor-like cells from human iPS cells (2013)
  • Author(s): 柳田絢加、伊藤慶一、近田裕美、中内啓光、紙谷聡英
  • Organizer: 第20回肝細胞研究会
  • Place of Presentation: 大阪国際会議場
• [Presentation] Mesenchymal progenitor cells in mouse fetal liver regulate differentiation and proliferation of hepatoblasts (2013)
  • Author(s): 伊藤慶一、柳田絢加、中内啓光、紙谷聡英
  • Organizer: 第20回肝細胞研究会
  • Place of Presentation: 大阪国際会議場
• [Presentation] ヒト多能性幹細胞からの二方向性分化能を有する肝前駆細胞の誘導 (2013)
  • Author(s): 紙谷聡英、中内啓光
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル
• [Presentation] REGULATION OF CYTOCHROME p450 3A11 EXPRESSION IN MOUSE HEPATIC PROGENITOR CELLS BY BCL-6 (2013)
  • Author(s): Hiromi Chikada, Keiichi Ito, Ayaka Yanagida, Hiromitsu Nakauchi, Akihide Kamiya
  • Organizer: The 11th Annual Meeting of International Society for Stem Cell
  • Place of Presentation: Reasearch Boston Convention and Exhibition Center,USA
• [Presentation] ヒト多能性幹細胞からの二方向性分化能を有する肝前駆細胞の誘導 (2013)
  • Author(s): 紙谷聡英、中内啓光
  • Organizer: 第49回日本肝臓学会総会
  • Place of Presentation: 京王プラザホテル（東京）
• [Presentation] REGULATION OF CYTOCHROME p450 3A11 EXPRESSION IN MOUSE HEPATIC PROGENITOR CELLS BY BCL-6 (2013)
  • Author(s): Hiromi Chikada, Keiichi Ito, Ayaka Yanagida, Hiromitsu Nakauchi, Akihide Kamiya
  • Organizer: 11th Annual Meeting of International Society of Stem Cell Reseach
  • Place of Presentation: Boston Convention and Exhibition Center, USA
• [Presentation] An in vitro expansion system in generating purified hepatic stem/progenitor-like cells derived from human iPS cells (2012)
  • Author(s): 紙谷聡英、伊藤慶一、柳田絢加、中内啓光
  • Organizer: 第35回日本分子生物学会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2012-12-11
• [Presentation] MEK-ERKシグナル経路による肝幹・前駆細胞の増殖制御機構 (2012)
  • Author(s): 紙谷聡英、伊藤慶一、柳田絢加、中内啓光
  • Organizer: 第19回肝細胞研究会
  • Place of Presentation: 札幌医科大学
  • Year and Date: 2012-06-29
• [Presentation] 肝幹・前駆細胞の長期増殖を制御する細胞内シグナル伝達機構 (2012)
  • Author(s): 紙谷聡英
  • Organizer: 第11回日本再生医療学会ランチョンセミナー
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2012-06-14
  • Invited
• [Presentation] The Application of Human iPS cells as an in vitro expansion system in generating purified Hepatic stem/progenitor-like cells to determine the molecular mechanisms regulating human liver orgagenesis (2012)
  • Author(s): 柳田絢加、紙谷聡英、伊藤慶一、中内啓光
  • Organizer: The 10th International Society of Stem Cell Research
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2012-06-14
• [Presentation] MEK activity regulates stem/progenitoer potential of fetal hepatoblasts through induction of cell cycle arrest (2012)
  • Author(s): 紙谷聡英、伊藤慶一、柳田絢加、中内啓光
  • Organizer: The 10th International Society of Stem Cell Research
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2012-06-14
• [Presentation] MEK-ERKシグナル伝達系による胎生肝幹・前駆細胞の増殖制御機構 (2012)
  • Author(s): 紙谷聡英、中内啓光
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: ホテル日航金沢
  • Year and Date: 2012-06-07
• [Presentation] MEK activity regulates stem/progenitoer potential of fetal hepatoblasts through induction of cell cycle arrest (2012)
  • Author(s): Akihide Kamiya
  • Organizer: 第10回 ISSCR
  • Place of Presentation: 横浜・パシフィコ横浜
• [Presentation] ヒト多能性幹細胞からの肝幹・前駆細胞分化誘導系の構築 (2011)
  • Author(s): 紙谷聡英、中内啓光
  • Organizer: 第15回肝臓学会大会(JDDW2011)
  • Place of Presentation: 福岡国際会議場
• [Presentation] 胎仔肝幹細胞の自己複製を制御する新規分子の探索とその機能解明 (2011)
  • Author(s): 伊藤慶一、紙谷聡英、岡田健、柳田絢加、伊東秀典、中内啓光
  • Organizer: 第18回肝細胞研究会
  • Place of Presentation: 東京ガーデンパレス
• [Presentation] 発生過程におけるcdk抑制因子p57による肝増殖制御機構 (2011)
  • Author(s): 柳田絢加,紙谷聡英,岡田健,伊藤慶一,伊東秀典,中内啓光
  • Organizer: 第18回肝細胞研究会
  • Place of Presentation: 東京ガーデンパレス
• [Presentation] ヒト多能性幹細胞からの長期増殖可能な肝前駆細胞の分化誘導 (2011)
  • Author(s): 紙谷聡英、柳田絢加、岡田健、伊藤慶一、中内啓光
  • Organizer: 第18回肝細胞研究会
  • Place of Presentation: 東京ガーデンパレス
• [Presentation] Prospective isolation and expansion of hepatoblast during early-fetal liver development in mice (2011)
  • Author(s): Okada Ken, Kamiya Akihide, Ito Keiichi, Yanagida Ayaka, Ito Hidenori, Kondou Hiroki, Nishina Hiroshi and Nakauchi Hiromitsu
  • Organizer: The 9th Annual Meeting of International Society for Stem Cell
  • Place of Presentation: Reasearch Toronto
• [Presentation] MEK-ERKシグナル伝達系による胎生肝幹・前駆細胞の増殖制御機構
  • Author(s): 紙谷聡英
  • Organizer: 第48回日本肝臓学会総会
  • Place of Presentation: 金沢・ホテル日航金沢
• [Presentation] 肝幹・前駆細胞の長期増殖を制御する細胞内シグナル伝達機構
  • Author(s): 紙谷聡英
  • Organizer: 第11回日本再生医療学会（ランチョンセミナー）
  • Place of Presentation: 横浜・パシフィコ横浜
  • Invited
• [Presentation] An in vitro expansion system in generating purified hepatic stem/progenitor-like cells derived from human iPS cells.
  • Author(s): 紙谷聡英
  • Organizer: 第35回日本分子生物学会
  • Place of Presentation: 福岡・福岡国際会議場
  • Invited
• [Book] 肝臓の再生医療に向けた幹細胞研究の進展」In The Frontiers in Life Sciences"幹細胞研究と再生医療" (2013)
  • Author(s): 紙谷聡英、近田裕美(中内博光編)
• [Book] 「肝臓の再生医療に向けた幹細胞研究の進展」 In The Frontiers in Life Sciences “幹細胞研究と再生医療“ （中内博光 編） (2013)
  • Author(s): 紙谷聡英、近田裕美
  • Publisher: 南山堂