ヒトiPS細胞由来機能性臓器の試験管内誘導へ向けた集学的アプローチ

• Project Area: Hyper Bio Assembler for 3D Celluler Innovation
• Project/Area Number: 26106721
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• 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): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2015: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000); Fiscal Year 2014: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
• Keywords: iPS細胞 / 器官原基 / 細胞外環境 / 再生医学

Outline of Annual Research Achievements

本研究提案では、申請者が独自開発したOrgan Bud Generation法を起点として、工学などさまざまな異分野の技術を融合し、発展型の培養系確立を目指している。
本年においては、まず細胞内・外環境の至適化を目指す研究において、著名な進展を認めた。すなわち、 Organ Bud形成における原理解明とその拡張性を実証し、A01,2班との連携による成果がCell Stem Cell５月号に表紙に採択されたほか、Nature Methods誌において特集記事が掲載された。さらに、新たな原著論文(Inside the Cell)がまもなく論文投稿予定であるほか、原理を体系化した総説論文(Developmental Biology)がまもなく受理予定である。
次に、A03班東北大グループとの連携による成果において、Liver Budを高機能化する酸素供給条件の明確化に成功し、現在論文投稿に向けた準備を進めている。さらに、A02班 名古屋大グループとの連携により、Organ Budの粘弾性評価系を確立することに成功した。これらの成果は、国際学会発表を行ったほか、論文投稿準備中である。その他、本領域における成果をまとめ、Regenerative Therapy誌に論文報告を行ったほか、Organ Bud形成に関する指導原理などを体系化した書籍を２編共同執筆した。
また、若手育成に関して著名な成果を認めた。本研究に携わった、博士学生らが学術振興会DC1やPDなど４つの研究助成金を獲得したほか、学会賞を６件受賞した。今後もこれらの成果を礎として、 Organ Bud Generation法の技術開発を継続していくことで、将来、移植医療や薬剤スクリーニングへの応用開発へと発展させる。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Autotransplantation of monkey ear perichondrium-derived progenitor cells for cartilage reconstruction. (2016)
  • Author(s): Kagimoto S, Takebe T*, Kobayashi S, Yabuki Y, Hori A, Hirotomi K, Mikami T, Uemura T, Maegawa J, Taniguchi H
  • Journal Title: Cell transplantation Volume: 25（5） Issue: 5 Pages: 951-962
  • DOI: 10.3727/096368916x690917
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Vascularized and Complex Organ Buds from Diverse Tissues via Mesenchymal Cell-Driven Condensation (2015)
  • Author(s): T. Takebe, M. Eomura, E. Yoshizawa, M. Kimura, H. Koike, Y. Ueno, T. Matsuzaki, T. Yamazaki, T. Toyohara, K. Osafune, H. Nakauchi, H. Y. Yoshikawa, H. Taniguchi
  • Journal Title: Cell Stem Cell Volume: 16 Issue: 5 Pages: 556-565
  • DOI: 10.1016/j.stem.2015.03.004
  • Peer Reviewed / Open Access
• [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 Issue: 10 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): Takanori Takebe*, Ran-Ran Zhang, Hiroyuki Koike, Masaki Kimura, Emi Yoshizawa, Masahiro Enomura, Keisuke Sekine, Hideki Taniguchi*(*: Correspondence)
  • Journal Title: Nature Protocols Volume: 9(2) Issue: 2 Pages: 396-409
  • DOI: 10.1038/nprot.2014.020
  • Peer Reviewed
• [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 Issue: 4 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 Issue: 8 Pages: 0-2
  • DOI: 10.1371/journal.pone.0104776
  • Peer Reviewed / Open Access
• [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 Issue: 4 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 Issue: 4 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 Issue: 4 Pages: 1247-1250
  • DOI: 10.1016/j.transproceed.2013.11.082
  • Peer Reviewed
• [Journal Article] The evidence of sophisticatedly heterogeneous population of human umbilical vein endothelial cells (2014)
  • Author(s): Zheng YW, Nie YZ, Tsuchida T, Zhang RR, Aoki K, Sekine K, Ogawa M, Takebe T, Ueno Y, Sakakibara H, Hirahara F, Taniguchi H
  • Journal Title: Transplant Proc Volume: 46 Issue: 4 Pages: 1251-3
  • DOI: 10.1016/j.transproceed.2013.11.077
  • Peer Reviewed / Open Access
• [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] The 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, and Taniguchi H
  • Journal Title: Stem Cells Dev Volume: (In press) Issue: 18 Pages: 2237-2249
  • DOI: 10.1089/scd.2013.0577
  • Peer Reviewed / Open Access
• [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, Nakata S, Ouchi R, Obana Y, Sekine K, Zheng YW, Takebe T, Isono K, Koseki H, Taniguchi H
  • Journal Title: Hepatology Volume: 印刷中 Issue: 1 Pages: 323-333
  • DOI: 10.1002/hep.27046
  • Peer Reviewed / Open Access
• [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 Issue: 4 Pages: 1191-3
  • DOI: 10.1016/j.transproceed.2013.12.026
  • Peer Reviewed / Open Access
• [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): Mitsuru Mizuno, Takanori Takebe, Shinji Kobayashi, Shintarou Kimura, Mamiko Masutani, Soojung Lee, Yong Hwa Jo, Jeong Ik Lee, Hideki Taniguchi
  • Journal Title: Transplant Proc, Volume: 46 Issue: 4 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(4) Issue: 4 Pages: 1201-4
  • DOI: 10.1016/j.transproceed.2013.12.021
  • Peer Reviewed
• [Journal Article] Engineering of human hepatic tissue with functional vascular networks (2014)
  • Author(s): Takebe T, Koike N, Sekine K, Fujiwara R, Amiya T, Zheng YW and Taniguchi H
  • Journal Title: Organogenesis Volume: 10(2)(Epub ahead of print) Issue: 2 Pages: 260-267
  • DOI: 10.4161/org.27590
  • Peer Reviewed
• [Journal Article] High-resolution intravital imaging for monitoring the transplanted islets 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 Issue: 4 Pages: 1166-1168
  • DOI: 10.1016/j.transproceed.2013.11.089
  • Peer Reviewed
• [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 Issue: 4 Pages: 1243-1246
  • DOI: 10.1016/j.transproceed.2013.11.086
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Generation of Diverse Organ Buds from Human iPSCs. (2016)
  • Author(s): Takebe T
  • Organizer: French Society for Cell and Gene Therapy
  • Place of Presentation: Marseille, France
  • Year and Date: 2016-03-14
  • Int'l Joint Research / Invited
• [Presentation] 血管構造を有する複雑なヒト臓器の人為的構成 (2015)
  • Author(s): 武部貴則
  • Organizer: 分生・生化学会
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] Generating diverse organ buds from stem cells. (2015)
  • Author(s): Takebe T
  • Organizer: JST CREST-PRESTO joint international symposium
  • Place of Presentation: 東京大学（東京都文京区）
  • Year and Date: 2015-11-05
  • Int'l Joint Research / Invited
• [Presentation] Human iPSC-derived organ bud based approaches. (2015)
  • Author(s): Takebe T
  • Organizer: 112th ITC(INTERNATIONAL TITISEE CONFERENCE
  • Place of Presentation: Mainz, Germany
  • Year and Date: 2015-09-22
  • Int'l Joint Research / Invited
• [Presentation] In vitro reconstructions and controls of multicellular structures. (2015)
  • Author(s): Takebe T
  • Organizer: The 26th CDB Meeting Mechanistic Perspectives of Multicellular Organization
  • Place of Presentation: 理化学研究所 多細胞システム形成研究センター（兵庫県神戸市）
  • Year and Date: 2015-09-08
  • Int'l Joint Research / Invited
• [Presentation] De novo generation of liver buds from stem cells. (2015)
  • Author(s): Takebe T
  • Organizer: International Conference of Future Hepatology at Kaohsiung
  • Place of Presentation: Kaohsiung, Taiwan
  • Year and Date: 2015-07-25
  • Int'l Joint Research / Invited
• [Presentation] De novo generation of diverse organ buds from iPSCs towards therapy. (2015)
  • Author(s): Takebe T
  • Organizer: ISSCR 2015 ANNUAL MEETING
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2015-06-26
  • Int'l Joint Research / Invited
• [Presentation] Realization of human iPSC-derived liver bud transplantation therapy. (2015)
  • Author(s): Takebe T
  • Organizer: the Young Investigators’ Stem Cell Symposium 2015
  • Place of Presentation: Biopolis, Singapore
  • Year and Date: 2015-06-08
  • Int'l Joint Research / Invited
• [Presentation] 臨床応用の基盤形成を目指した肝再生研究の新展開 (2015)
  • Author(s): 武部貴則
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
  • Year and Date: 2015-05-22
  • Invited
• [Presentation] Regenerative approaches through developmental biology. (2015)
  • Author(s): Takebe T
  • Organizer: EASL, 50th the International Liver Congress
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2015-04-22
  • Int'l Joint Research / Invited
• [Presentation] Human iPSC-derived organ bud based approaches towards clinical application. (2015)
  • Author(s): Takebe T
  • Organizer: 8th Pan Pacific Symposium 2015 on Stem Cells and Cancer Research
  • Place of Presentation: Hsinchu, Taiwan
  • Year and Date: 2015-04-11
  • Int'l Joint Research
• [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
  • 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
  • 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
  • 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
  • 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（熊本県）
  • Year and Date: 2014-09-04 – 2014-09-05
  • Invited
• [Presentation] Vascularized and functional human liver from an iPSC-derived organ bud transplant. (2014)
  • Author(s): Takebe T
  • 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
  • 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, USA
  • 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 – 2014-04-14
  • Invited
• [Book] Engineering pancreatic tissues from stem cells towards therapy. (2016)
  • Author(s): Takahashi Y, Takebe T, Taniguchi H
  • Total Pages: 9
  • Publisher: Regenerative Therapy
• [Book] iPS由来器官原基移植による機能的なヒト肝臓の創出 (2015)
  • Author(s): 谷口英樹、武部貴則
  • Total Pages: 18
  • Publisher: 最新医学
• [Book] 肝胆膵 (2015)
  • Author(s): 谷口英樹、武部貴則
  • Total Pages: 8
  • Publisher: アークメディア
• [Book] 月刊 糖尿病 DIABETES (2015)
  • Author(s): 谷口英樹、武部貴則
  • Total Pages: 7
  • Publisher: 医学出版
• [Book] 膵島の再生医療－膵β細胞の発生と再生をめぐる新展開－ (2015)
  • Author(s): 谷口英樹、武部貴則
  • Total Pages: 5
  • Publisher: 診断と治療
• [Book] Annual Review 2015 糖尿病・代謝・内分泌 (2015)
  • Author(s): 武部貴則、谷口英樹
  • Total Pages: 6
  • Publisher: 中外医学
• [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): 武部貴則、谷口英樹
  • 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. (2014)
  • Author(s): Rashid T, Takebe T, Nakauchi H
  • Total Pages: 3
  • Publisher: Gut
• [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] 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): 14.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
• [Patent(Industrial Property Rights)] 培養方法及び細胞塊 (2015)
  • Inventor(s): 谷口英樹、武部貴則、江尻洋子
  • Industrial Property Rights Holder: 公立大学法人横浜市立大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-05-29
  • Overseas
• [Patent(Industrial Property Rights)] 細胞培養システム (2015)
  • Inventor(s): 谷口英樹、武部貴則、関根圭輔、砂山裕信、西村哲也、中尾敦
  • Industrial Property Rights Holder: 公立大学法人横浜市立大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-09-18
  • Overseas
• [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
  • 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
  • Filing Date: 2014-05-29