ヒトｉＰＳ細胞を用いた革新的三次元肝・膵組織創出法の開発

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24689052
• Research Institution: Yokohama City University
• Principal Investigator: 武部 貴則 横浜市立大学, 医学部, 准教授 (20612625)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 再生医学

Outline of Annual Research Achievements

本年度では、このようなヒト肝臓原基の人為的構成法の拡張を目指し、膵臓を含む他器官の構成系への活用可能性を検討した。具体的には、研究代表者らが開発した手法により、マウス膵β細胞株、マウス胎児膵臓細胞、マウス・ヒト膵島組織などのいずれにおいても、３次元的な膵臓原基の作製が実現できることを示した。さらに、腎組織など他器官の再構成系としても利用できることを発見した。一方、血管系を含む本培養系を用いることで、インスリン分泌機能や、移植後の生着効率に優れることを確認した。治療効果の検証を目的として、免疫不全状態で膵β細胞が選択的・特異的に破壊される Insulin-TRECK-scidマウスへの移植実験を行ったところ、膵臓原基の異所性移植群において、肝不全モデルマウスの生存率が著名に改善することを見出した。ヒトiPS由来膵臓内胚葉細胞については、他グループの既報プロトコルを用いて作製したところ充分な機能性は確認されなかったものの、移植可能な組織形成が可能であることを示したことから、今後再現性の高いプロトコルが確立され次第、本培養系の優位性が示されるものと期待される。成果の一部は本年度において、著名な学術雑誌であるCell Stem Cell誌（in press）に受理され、その他の成果も論文発表を準備中である。
器官原基を移植する、という新たな治療概念によって、従来の細胞を移植するという治療を凌駕する革新的な再生医療を提供できるものと大いに期待される。本法を基盤技術として、本研究が対象としている膵臓をはじめ様々なヒト臓器構成系を開発していくことにより、将来的に莫大な社会的医療ニーズに応え、多くの患者を救済することが可能な再生医療実現化へ向けて革新的な手法を確立できるものと大いに期待される。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Causes of Carryover

26年度が最終年度であるため、記入しない。

Expenditure Plan for Carryover Budget

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Transient vascularization of transplanted human adult–derived progenitors promotes self-organizing cartilage. (2014)
  • Author(s): Takebe T *, Kobayashi S, Suzuki H, Mizuno M, Chang YM, Yoshizawa E, Kimura M, Hori A, Asano J, Maegawa J, Taniguchi H
  • Journal Title: Journal of Clinical Investigation Volume: 124 Pages: 4325-4334
  • DOI: 10.1172/JCI76443
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant. (2014)
  • Author(s): Takebe T*, Zhang RR, Koike H, Kimura M, Yoshizawa E, Enomura M, Sekine K, Taniguchi H*
  • Journal Title: Nature Protocols Volume: 9 Pages: 396-409
  • DOI: 10.1038/nprot.2014.020
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effect of cryopreservation and cell passage number on cell preparations destined for autologous chondrocyte transplantation. (2014)
  • Author(s): Nam BM, Kim BY, Jo YH, Lee S, Nemeno JG, Yang W, Lee KM, Kim H, Jang IJ, Takebe T, Lee JI
  • Journal Title: Transplant Proc Volume: 46 Pages: 1145-1149
  • DOI: 10.1016/j.transproceed.2013.11.117.
  • Peer Reviewed
• [Journal Article] Polycomb Group Protein Ezh2 Regulates Hepatic Progenitor Cell Proliferation and Differentiation in Murine Embryonic Liver. (2014)
  • Author(s): Koike H, Ouchi R, Ueno Y, Nakata S, Obana Y, Sekine K, Zheng YW, Takebe T, Isono K, Koseki H, Taniguchi H
  • Journal Title: PloS one Volume: 9 Pages: 0-2
  • DOI: 10.1371/journal.pone.0104776
  • Peer Reviewed
• [Journal Article] Effect of Preservation Conditions on Cartilage Tissue for Cell Transplantation. (2014)
  • Author(s): Kim BY, Nam BM, Lee KM, Jo YH, Nemeno JG, Yang W, Lee S, Kim H, Jang IJ, Takebe T, Lee JI
  • Journal Title: Transplant Proc Volume: 46 Pages: 1139-1144
  • DOI: 10.1016/j.transproceed.2013.11.125.
  • Peer Reviewed
• [Journal Article] Artificial Islets From Hybrid Spheroids of Three Pancreatic Cell Lines. (2014)
  • Author(s): Jo YH, Jang IJ, Nemeno JG, Lee S, Kim BY, Nam BM, Yang W, Lee KM, Kim H, Takebe T, Kim YS, Lee JI
  • Journal Title: Transplant Proc Volume: 46 Pages: 1156-1160
  • DOI: 10.1016/j.transproceed.2013.11.074.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of Natural Cartilaginous Extracellular Matrix on Chondrogenic Potential for Cartilage Cell Transplantation. (2014)
  • Author(s): Yang W, Lee S, Jo YH, Lee KM, Nemeno JG, Nam BM, Kim BY, Jang IJ, Kim HN, Takebe T, Lee JI
  • Journal Title: Transplant Proc Volume: 46 Pages: 1247-1250
  • DOI: 10.1016/j.transproceed.2013.11.082.
  • Peer Reviewed
• [Journal Article] Evidence of a Sophisticatedly Heterogeneous Population of Human Umbilical Vein Endothelial Cells. (2014)
  • Author(s): Zheng YW, Nie YZ, Tsuchida T, Zhang, Aoki K, Sekine K, Ogawa M, Takebe T, Ueno Y, Sakakibara H, Hirahara F, Taniguchi H
  • Journal Title: Transplant Proc Volume: 46 Pages: 1251-1253
  • DOI: 10.1016/j.transproceed.2013.11.077.
  • Peer Reviewed
• [Journal Article] Fluorescent Labeling and Visualization of Human Induced Pluripotent Stem Cells With the Use of Transcription Activator–like Effector Nucleases. (2014)
  • Author(s): Sekine K, Takebe T, Taniguchi H
  • Journal Title: Transplant Proc Volume: 46 Pages: 1205-1207
  • Peer Reviewed
• [Journal Article] he CD133+CD44+ Precancerous Subpopulation of Oval Cells Is a Therapeutic Target for Hepatocellular Carcinoma (2014)
  • Author(s): Zheng YW, Tsuchida T, Shimao T, Li B, Takebe T, Zhang RR, Sakurai Y, Ueno Y, Sekine K, Ishibashi N, Imajima M, Tanaka T, Taniguchi H
  • Journal Title: Stem Cells and Development Volume: 23 Pages: 2237-2249
  • DOI: 10.1089/scd.2013.0577.
  • Peer Reviewed
• [Journal Article] Ring1B Promotes Hepatic Stem/Progenitor Cell Expansion via Simultaneous Suppression of Cdkn1a and Cdkn2a. (2014)
  • Author(s): Koike H, Ueno Y, Naito T, Shiina T, Ouchi R, Obana Y, Mori M, Sekine K, Takebe T, Zheng YW, Isono K, Koseki H, Taniguchi H
  • Journal Title: Hepatology Volume: 60 Pages: 323-333
  • DOI: 10.1002/hep.27046.
  • Peer Reviewed
• [Journal Article] The development of humanized liver with Rag1 knockout rats. (2014)
  • Author(s): Tsuchida T, Zheng YW, Zhang RR, Takebe T, Ueno Y, Sekine K, Taniguchi H
  • Journal Title: Transplant Proc Volume: 46 Pages: 1191-1193
  • DOI: 10.1016/j.transproceed.2013.12.026.
  • Peer Reviewed
• [Journal Article] Tropism of cancer stem cells to a specific distant organ. (2014)
  • Author(s): Okuda R, Sekine K, Hisamatsu D, Ueno Y, Takebe T, Zheng YW, Taniguchi H
  • Journal Title: In Vivo Volume: 28 Pages: 361-365
  • Peer Reviewed
• [Journal Article] Elastic cartilage reconstruction by transplantation of cultured hyaline cartilage-derived chondrocytes. (2014)
  • Author(s): Mizuno M, Takebe T*, Kobayashi S, Kimura S, Masutani M, Lee S, Jo YH, Lee JI, Taniguchi H*
  • Journal Title: Transplant Proc Volume: 46 Pages: 1217-1221
  • DOI: 10.1016/j.transproceed.2013.12.006.
  • Peer Reviewed
• [Journal Article] Identification of Proliferating Human Hepatic Cells from Human Induced Pluripotent Stem Cells. (2014)
  • Author(s): Zhang RR Takebe T*, Sekine K, Koike H, Zheng YW Taniguchi H*
  • Journal Title: Transplant Proc Volume: 46 Pages: 1201-1204
  • DOI: 10.1016/j.transproceed.2013.12.021.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Engineering of human hepatic tissue with functional vascular networks. (2014)
  • Author(s): 17.Takebe T*, Koike N*, Sekine K, Fujiwara R, Amiya T, Zheng YW, Taniguchi H*
  • Journal Title: Organogenesis Volume: 10 Pages: 260-267
  • DOI: 10.4161/org.27590
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] High-resolution intravital imaging for monitoring the transplanted islet in mice. (2014)
  • Author(s): Takahashi Y, Takebe T*, Enomura M, Koike N, Lee S, Nemeno JG, Sekine K, Lee JI, Taniguchi H*
  • Journal Title: Transplant Proc Volume: 46 Pages: 1166-1168
  • DOI: 10.1016/j.transproceed.2013.11.089.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Self-Formation of Vascularized Hepatic Tissue from Human Adult Hepatocyte. (2014)
  • Author(s): Enomoto Y, Enomura M, Takebe T*, Mitsuhashi Y, Kimura M, Yoshizawa E, Taniguchi H*
  • Journal Title: Transplant Proc Volume: 46 Pages: 1243-1246
  • DOI: 10.1016/j.transproceed.2013.11.086.
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Liver organogenesis. (2015)
  • Author(s): Takebe T
  • Organizer: ASTELLAS FRANCE Annual Meeting of Transplantation Club
  • Place of Presentation: Lille, France
  • Year and Date: 2015-02-06 – 2015-02-06
  • Invited
• [Presentation] Transient vascularization of transplanted human adult-derived progenitors promotes self-organizing cartilage. (2014)
  • Author(s): Takebe T
  • Organizer: Asian Cartilage Repair Society 2nd Annual Congress
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2014-12-07 – 2014-12-07
  • Invited
• [Presentation] 臨床応用へ向けたiPS細胞由来ヒト臓器原基操作技術の開発 (2014)
  • Author(s): 武部貴則
  • Organizer: 第41回日本臓器保存生物医学会学術集会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府）
  • Year and Date: 2014-11-28 – 2014-11-28
  • Invited
• [Presentation] 器官発生初期プロセスの再現による複雑なヒト臓器の人為的構成 (2014)
  • Author(s): 武部貴則
  • Organizer: 第37回日本分子生物学会年会シンポジウム
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-11-25 – 2014-11-27
  • Invited
• [Presentation] Realization of iPSC-Organ Bud Transplantation Therapy. (2014)
  • Author(s): Takebe T
  • Organizer: World Alliance forum
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2014-11-06 – 2014-11-07
  • Invited
• [Presentation] Vascularized and functional human liver from an iPSC-derived organ bud transplant. (2014)
  • Author(s): Takebe T
  • Organizer: Advances and Applications of Functional Hepatocytes Symposium
  • Place of Presentation: Shanghai, China
  • Year and Date: 2014-10-29 – 2014-10-30
  • Invited
• [Presentation] Pluripotent stem cells and organ reconstitution for rare diseases (2014)
  • Author(s): Takebe T
  • Organizer: Translational Science of Rare Diseases – From Rare to Care II
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-10-08 – 2014-10-10
  • Invited
• [Presentation] 多細胞系からなる複雑なヒト臓器の人為的構成 (2014)
  • Author(s): 武部貴則
  • Organizer: 第66回日本生物工学会大会
  • Place of Presentation: 札幌コンベンションセンター（北海道）
  • Year and Date: 2014-09-10 – 2014-09-10
  • Invited
• [Presentation] Vascularized and functional human liver from an iPSC-derived organ bud transplant. (2014)
  • Author(s): Takebe T
  • Organizer: KEY Forum: From Stem Cells to Organs
  • Place of Presentation: 熊本市医師会館（熊本）
  • Year and Date: 2014-09-04 – 2014-09-04
  • Invited
• [Presentation] Vascularized and functional human liver from an iPSC-derived organ bud transplant. (2014)
  • Author(s): 武部貴則
  • Organizer: 47th Annual Meeting for the Japanese Society of Developmental Biologists
  • Place of Presentation: WINC AICHI（愛知県）
  • Year and Date: 2014-05-28 – 2014-05-28
  • Invited
• [Presentation] Realization of human iPSC-derived organ bud transplantation therapy. (2014)
  • Author(s): Takebe T
  • Organizer: The Whole Liver Replacement State-of-the-Science Summit
  • Place of Presentation: Chicago, America
  • Year and Date: 2014-04-29 – 2014-04-30
  • Invited
• [Presentation] Vascularized and functional human liver from an iPSC-derived organ bud transplant. (2014)
  • Author(s): Takebe T
  • Organizer: 7th Pan Pacific Symposium on Stem Cells and Cancer Research (PPSSC)
  • Place of Presentation: Taichung, Taiwan
  • Year and Date: 2014-04-12 – 2014-04-17
  • Invited
• [Book] iPS細胞由来器官原基の人為的構成に基づくヒト肝臓の創出 (2014)
  • Author(s): 武部貴則、谷口英樹
  • Total Pages: 4
  • Publisher: 横浜医学
• [Book] 幹細胞と微小環境の相互作用に基づくヒト3次元組織の人為的再構成 (2014)
  • Author(s): 谷口英樹、武部貴則
  • Total Pages: 5
  • Publisher: がん分子標的治療
• [Book] 多能性幹細胞を用いた膵β細胞分化誘導研究の最新動向 (2014)
  • Author(s): 高橋禎暢、武部貴則、谷口英樹
  • Total Pages: 8
  • Publisher: Organ Biology
• [Book] Novel strategies for liver therapy using stem cells. Gut, 2014 3ページ 11.Takebe T, Taniguchi (2014)
  • Author(s): Rashid T, Takebe T, Nakauchi H
  • Total Pages: 3
  • Publisher: Clinical Pharmacology Therapeutics
• [Book] ヒトiPS細胞を活用した再生医療の開発戦略 (2014)
  • Author(s): 谷口英樹、武部貴則
  • Total Pages: 2
  • Publisher: 消化器外科
• [Book] ヒト代謝性臓器の創出に向けた開発戦略 (2014)
  • Author(s): 谷口英樹、武部貴則
  • Total Pages: 9
  • Publisher: 最新医学
• [Book] ヒト臓器の人為的構成に基づく肝細胞の分化誘導 ES・iPS細胞実験スタンダード―再生・創薬・疾患研究のプロトコールと臨床応用の必須知識 (2014)
  • Author(s): 武部貴則、関根圭輔、谷口英樹
  • Total Pages: 10
  • Publisher: 羊土社
• [Book] Human iPSC-Derived Miniature Organs: A Tool for Drug Studies. (2014)
  • Author(s): Takebe T*, Taniguchi H
  • Total Pages: 3
  • Publisher: Clinical Pharmacology & Therapeutics
• [Book] Novel strategies for liver therapy using stem cells. (2014)
  • Author(s): Rashid T, Takebe T, Nakauchi H
  • Total Pages: 3
  • Publisher: Gut
• [Patent(Industrial Property Rights)] 原始腸内胚葉細胞及びその作製方法 (2014)
  • Inventor(s): 武部貴則(40%)、張冉冉(10%)、谷口英樹(50%)
  • Industrial Property Rights Holder: 武部貴則(40%)、張冉冉(10%)、谷口英樹(50%)
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-248694
  • Filing Date: 2014-12-08
• [Patent(Industrial Property Rights)] 培養方法及び細胞塊 (2014)
  • Inventor(s): 江尻洋子(10%)、谷口英樹(50%)、 武部貴則(40%)
  • Industrial Property Rights Holder: 江尻洋子(10%)、谷口英樹(50%)、 武部貴則(40%)
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2014-112959
  • Filing Date: 2014-05-29