誘導多能性幹(iPS)細胞を用いた新しい移植用心筋前駆細胞の開発

• Project/Area Number: 20659125
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Kyoto University
• Principal Investigator: 山下 潤 Kyoto University, 再生医科学研究所, 准教授 (50335288)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2009: ¥1,600,000 (Direct Cost: ¥1,600,000); Fiscal Year 2008: ¥1,600,000 (Direct Cost: ¥1,600,000)
• Keywords: iPS細胞 / 心筋再生 / 細胞治療 / 心筋前駆細胞 / サイクロスポリンA / ES細胞

Research Abstract

本研究は、応募者がこれまでES細胞研究において蓄積したノウハウ及び新しい知見をiPS細胞に適里することにより、将来の心筋再生医療に応用可能な強力な心筋再生能を有する新しい心筋前駆細胞を分化誘導・純化する方法を開発し、心筋再生医療を実現することを目的とする。研究期間内においては、1)iPS細胞を用いた心筋分化系の構築、2)iPS細胞における心筋前駆細胞の同定、3)iPS細胞における心筋前駆細胞の特異的分化誘導と純化、4)iPS細胞由来心筋前駆細胞の動物モデルへの移植実験、5)GMP(good manufacturing practice)基準での細胞調製に向けた分化誘導・純化法の改良、の5項目の検討を行う。これらの研究により、新しい移植用心筋前駆細胞を開発する。平成21年度は、マウス人工多能性幹細胞(iPS細胞)を用いた心血管分化誘導システムの構築:我々が構築してきたマウスES細胞分化システムを導入し、マウスES細胞と同様に系統的な心血管分化誘導に成功した(Narazaki, Circulation, 2008)。ヒトiPS細胞を用いた心血管分化誘導:すでに自己拍動する機能的心筋細胞の誘導に成功している。マウスES細胞からの高効率心筋前駆細胞及び心筋細胞分化誘導法の開発:免疫抑制剤サイクロスポリンA(CSA)が強力な心筋前駆細胞及び心筋細胞の分化誘導効果を有していることを見出した。CSAによりこれら心筋系列細胞の誘導効率は約10-20倍増加し、潤沢な心筋前駆細胞の採集が可能となった。新しい心筋前駆細胞治療の可能性を拓いた(Yan, Biochem Biophys Res Commun, 2009)。Narazakiの論文は2008年Circulation誌基礎生物学部門の最優秀論文賞に選ばれた。Yanは日本循環器学会国際留学生YIAを受賞した。このように本研究は国内外で高い評価を受けている。

Research Products

• [Journal Article] Convergence of Notch and β-catenin signaling induces arterial fate in vascular progenitors. (2010)
  • Author(s): Yamamizu K, Matsunaga T, Uosaki H, Fukushima H, Katayama S, Hiraoka-Kanie M, Mitani K, Yamashita JK.
  • Journal Title: J Cell Biol 189 Pages: 353-367
  • Peer Reviewed
• [Journal Article] Enhancement of vascular progenitor potential by protein kinase A through dual induction of Flk-1 and Neuropilin-1 (2009)
  • Author(s): Yamamizu K, Kawasaki K, Katayama S, Watabe T, Yamashita JK.
  • Journal Title: Blood 114 Pages: 3707-3716
  • Peer Reviewed
• [Journal Article] Cyclosporin-A potently induces highly cardiogenic progenitors from embryonic stem cells (2009)
  • Author(s): Yan P, Nagasawa A, Uosaki H, Sugimoto A, Yamamizu K, Teranishi M, Matsuda H, Matsuoka S, Ikeda T, Komeda M, Sakata R, Yamashita JK.
  • Journal Title: Biochem Biophys Res Commun 379 Pages: 115-120
  • Peer Reviewed
• [Journal Article] Cyclosporin-A potently induces highly cardiogenic progenitors from embryonic stem cells. (2009)
  • Author(s): Yan P, Nagasawa A. Uosaki H. Sugimoto A, Yamamizu K. Teranishi M, Matsuda R Matsuoka S, Ikeda T. Komeda M, Sakata R. Yamashita JK*.
  • Journal Title: Biochem Biophys Res Commun 379 Pages: 115-120
  • Peer Reviewed
• [Journal Article] Creations of biological pacemaker (2009)
  • Author(s): Narazaki G, Yamashita JK.
  • Journal Title: Inflammation and Regeneration. 29 Pages: 123-127
• [Journal Article] Directed and systematic differentiation of cardiovascular cells from mouse induced pluripotent stem cells. (2008)
  • Author(s): Narazaki G. Uosaki M, Teranishi M, Okita K, Kin B, Matsuoka S, Yamanaka S, Yamashita JK*.
  • Journal Title: Circulation 118 Pages: 498-506
  • Peer Reviewed
• [Journal Article] Evaluation of antiangiogenic activity of azumamides by the in vitro vascular organization model using mouse induced pluripotent stem (iPS) cells. (2008)
  • Author(s): Nakao Y*. Narazaki G. Hoshino I. Maeda S. Yoshida M, Maejima H, Yamashita JK*
  • Journal Title: Bioorg Med Chem Lett 18 Pages: 2982-2984
  • Peer Reviewed
• [Journal Article] Augmentation of neovasculanzaiton in hindlimb ischemia by combined transplantation of human embryonic stem cells-derived endothelial and mural cells. (2008)
  • Author(s): Yamahara K, Sone M. Itoh H, Yamashita JK. Yurugi-Kobayashi T, Homma K, Chao TH, Miyashita K, Park K, Oyamada N, Sawada N, Taura D, Tamura X, Xakao K.
  • Journal Title: PLoS One 3
  • Peer Reviewed
• [Journal Article] Identification of adherens junction-associated GTPase activating proteins by the fluorescence localization-based expression cloning. (2008)
  • Author(s): Matsuda M, Kobayashi Y, Masuda S, Adachi M. Watanabe T. Yamashita JK, Nishi E, Tsukita S, Furuse M.
  • Journal Title: Exp Cell Res 314 Pages: 939-949
  • Peer Reviewed
• [Journal Article] Cyclic strain induces mouse embryonic stem cell differentiation into vascular smooth muscle cells by activating PDGF receptor {beta}. (2008)
  • Author(s): Shimizu N. Yamamoto K. Obi S. Kumagaya S. Masumura T, Shimano Y, Naruse K, Yamashita JK, Igarashi T, Ando J.
  • Journal Title: J Appl Physiol 104 Pages: 766-772
  • Peer Reviewed
• [Presentation] iPS cells for cardiovascular research (2009)
  • Author(s): 山下潤
  • Organizer: JSPS presents, Sweden-Japan Joint Colloquium, "Advances in Cellular Reprogramming and Stem Cell Biology" (invited)
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2009-09-05
• [Presentation] Cardiovascular cell differentiation and diversification from ES and iPS cells (2009)
  • Author(s): 山下潤
  • Organizer: KSMBMB 2009 Annual International Conference, Symposium "Cardiogenesis, Angiogenesis, and Lymphangiogenesis" (invited)
  • Place of Presentation: Seoul, Korea
• [Presentation] Vascular cell differentiation & diversification from ES and WS cells (2009)
  • Author(s): 山下潤
  • Organizer: The 7^<th> Korea-Japan Joint Symposium on Vascular Biology (invited)
  • Place of Presentation: Seoul, Korea
• [Presentation] Cardiovascular cell differentiation from ES and iPS cells (2009)
  • Author(s): 山下潤
  • Organizer: EMBO Workshop, Lymphatic and Blood Vasculature : from models to human disease (invited)
  • Place of Presentation: Helsinki, Finland
• [Presentation] ES細胞及びiPS細胞を用いた血管分化・多様化・再生機構の解析 (2009)
  • Author(s): 山下潤
  • Organizer: 日本内分泌学会シンポジウム「血管新生と心血管系内分泌の新展開」
  • Place of Presentation: 前橋
• [Presentation] ES細胞及びiPS細胞を用いた心血管分化再生研究 (2008)
  • Author(s): Yamashita JK.
  • Organizer: 私学理科研究会二学期例会(招請講演)
  • Place of Presentation: 京都
  • Year and Date: 2008-12-25
• [Presentation] ES細胞及びiPS細胞を用いた心血管分化再生研究. (2008)
  • Author(s): Yamashita JK.
  • Organizer: 熊本Science Frontier研究会 (特別講演)
  • Place of Presentation: 熊本
  • Year and Date: 2008-12-10
• [Presentation] ES細胞及びiPS細胞からの心血管分化 (2008)
  • Author(s): Yamashita JK.
  • Organizer: BMB2008シンポジウム : 1S1 多能性幹細胞を規定する因子群-臨床応用を見据えて- (招請講演)
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] Research for vascular development and regeneration using ES and iPS cells. (2008)
  • Author(s): Yamashita JK.
  • Organizer: The 24th Kumamoto Medical Bioscience Symposium "Frontiers of Vascular Medical Science and Innovative Therapy" (invited).
  • Place of Presentation: Kumamoto
  • Year and Date: 2008-11-27
• [Presentation] Specific Expansion of Cardiac Progenitors and Cardiomyocytes from ES and iPS Cells. (2008)
  • Author(s): Yamashita JK.
  • Organizer: The Second International Cell Therapy Conference (invited)
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2008-11-20
• [Presentation] 幹細胞と再生医学-心臓や血管は再生できるか-. (2008)
  • Author(s): 山下潤
  • Organizer: 京都南ロータリークラブ講演会(招請講演)
  • Place of Presentation: 京都
  • Year and Date: 2008-10-16
• [Presentation] ES細胞及びiPS細胞を用いた心血管分化再生研究. (2008)
  • Author(s): 山下潤
  • Organizer: 佐賀・生活習慣病フォーラム2008 (特別講演)
  • Place of Presentation: 佐賀
  • Year and Date: 2008-08-02
• [Presentation] ES細胞及びiPS細胞を用いた心血管分化再生研究. (2008)
  • Author(s): 山下潤
  • Organizer: 心血管再生先端治療フォーラム (特別講演)
  • Place of Presentation: 東京
  • Year and Date: 2008-07-05
• [Presentation] ES 細胞およびiPS細胞を用いた心血管分化再生研究. (2008)
  • Author(s): 山下潤
  • Organizer: 第1回臨床研究フォーラム (招請講演)
  • Place of Presentation: 御殿場
• [Presentation] Molecular mechanisms of arterial-venous specification. (2008)
  • Author(s): Yamashita JK.
  • Organizer: 第16回日本血管生物医学会・日韓合同血管生物シンポジウム (invited).
  • Place of Presentation: 金沢
• [Book] Recent Advances in Thrombosis and Hemostasis 2008. Part5 (2008)
  • Author(s): Yamashita JK.
  • Publisher: Springer
• [Remarks] 京都大学 再生医科学研究所 附属幹細胞医学研究センター 幹細胞分化制御研究領域
  • URL: http://www.frontier.kyoto-u.ac.jp/es02/
• [Remarks] 京都大学 再生医科学研究所 附属幹細胞医学研究センター幹細胞分化制御研究領域
  • URL: http://www.frontier.kyoto-u.ac.jp/es02/
• [Patent(Industrial Property Rights)] Efficieni production and use of highly cardiogenic progenitors and cardiomyocyles from embryonic and iaduced pluripotent stem cells (2008)
  • Inventor(s): 山下潤顔, 培実
  • Industrial Property Rights Holder: 京都大学
  • Filing Date: 2008-08-29
  • Overseas