Drug discovery for the treatment of severe heart failure

• Project/Area Number: 25293297
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular surgery
• Research Institution: Kyoto University
• Principal Investigator: Tsuneyosi Hiroshi 京都大学, 医学(系)研究科(研究院), その他 (40645412)
• Co-Investigator(Kenkyū-buntansha): SAKATA RYUZO 京都大学, 大学院医学研究科, 名誉教授 (20325781) ; 丸井 晃 京都大学, 医学(系)研究科(研究院), 非常勤講師 (60402856) ; 升本 英利 京都大学, 医学(系)研究科(研究院), 助教 (70645754)
• Co-Investigator(Renkei-kenkyūsha): YAMASHITA JUN 京都大学, ips細胞研究所, 教授 (50335288)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2015: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2013: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 心筋疾患外科学 / iPS細胞 / 創薬スクリーニング / 心筋症 / 重症心不全 / 創薬研究

Outline of Final Research Achievements

With regards to the establishment of cardiomyopathy patient’s iPS cells, we planned to collect the myocardial tissue intraoperatively in order to recognize the characteristics of pathology. And we carried out sampling in one case. With regards to iPS cell-derived cardiac tissue sheet, we differentiated cardiomyocytes and mural cells individually and made the sheets by mixing them in strict ratio. With regards to method of drug screening, we measured extracellular electrical potentials on the multi-electrode device. We focused on the assessment of cardio toxicity and used the E4031 that caused drug-induced QT prolongation. We reproduced QT (FPD: field potential duration) prolongation and characteristic re-entry type arrhythmia visually.

Research Products

• [Journal Article] Green Tea Polyphenol Prevents Diabetic Rats From Acute Kidney Injury After Cardiopulmonary Bypass. (2016)
  • Author(s): Funamoto M, Masumoto H, Takaori K, Taki T, Setozaki S, Yamazaki K, Minakata K, Ikeda T, Hyon SH, Sakata R.
  • Journal Title: Ann Thorac Surg Volume: 101 Issue: 4 Pages: 1507-13
  • DOI: 10.1016/j.athoracsur.2015.09.080
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Efficient long-term survival of cell grafts after myocardial infarction with thick viable cardiac tissue entirely from pluripotent stem cells. (2015)
  • Author(s): Matsuo T, Masumoto H, Tajima S, Ikuno T, Katayama S, Minakata K, Ikeda T, Yamamizu K, Tabata Y, Sakata R, Yamashita JK.
  • Journal Title: Scientific Reports Volume: 5:16842 Issue: 1 Pages: 1-14
  • DOI: 10.1038/srep16842
  • NAID: 120005753829
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration. (2014)
  • Author(s): Masumoto H, Ikuno T, Takeda M, Fukushima H, Marui A, Katayama S, Shimizu T, Ikeda T, Okano T, Sakata R, Yamashita JK.
  • Journal Title: Sci Rep Volume: 4 Issue: 1 Pages: 6716-6716
  • DOI: 10.1038/srep06716
  • Peer Reviewed / Open Access
• [Journal Article] Effects of hepatocyte growth factor in myocarditis rats induced by immunization with porcine cardiac myosin. (2014)
  • Author(s): Nakano J, Ikeda T, Sakata R et al.
  • Journal Title: Interact Cardiovasc Thorac Surg Volume: 18 Issue: 3 Pages: 300-307
  • DOI: 10.1093/icvts/ivt512
  • Peer Reviewed
• [Journal Article] Effect of microRNA-145 to prevent vein graft disease in rabbits by regulation of smooth muscle cell phenotype. (2014)
  • Author(s): Ohnaka M, Ikeda T, Sakata R et al.
  • Journal Title: J Thorac Cardiovasc Surg. Volume: 印刷中 Issue: 2 Pages: 676-682.e2
  • DOI: 10.1016/j.jtcvs.2013.11.054
  • Peer Reviewed
• [Journal Article] Identification of chemicals inducing cardiomyocyte proliferation in developmental stage-specific manner with pluripotent stem cells (2013)
  • Author(s): Uosaki H, Magadum A, Seo K, Fukushima H, Takeuchi A, Nakagawa Y, Moyes KW, Narazaki G, Kuwahara K, Laflamme M, Matsuoka S, Nakatsuji N, Nakao K, Kwon C, Kass DA, Engel FB, Yamashita JK
  • Journal Title: Circ Cardiovasc Genet Volume: 6(6) Issue: 6 Pages: 624-33
  • DOI: 10.1161/circgenetics.113.000330
  • Peer Reviewed
• [Journal Article] Prevention of retrosternal adhesion by novel biocompatible glue derived from food additives. (2013)
  • Author(s): Kamitani T, Ikeda T, Sakata R et al.
  • Journal Title: J Thorac Cardiovasc Surg Volume: 146 Issue: 5 Pages: 1232-1238
  • DOI: 10.1016/j.jtcvs.2013.02.001
  • Peer Reviewed
• [Journal Article] Strategies in cell therapy for cardiac regeneration (2013)
  • Author(s): Masumoto H
  • Journal Title: Inflammation and Regeneration Volume: 33 Issue: 2 Pages: 114-120
  • DOI: 10.2492/inflammregen.33.114
  • NAID: 130004943839
  • ISSN: 1880-8190, 1880-9693
  • Peer Reviewed
• [Presentation] ブタ心筋梗塞モデルを用いたiPS細胞由来心臓組織シート移植による不整脈評価実験 (2015)
  • Author(s): 幾野 毅、坂田隆造、山下潤 他
  • Organizer: 第37回日本バイオマテリアル学会大会
  • Place of Presentation: 京都市
  • Year and Date: 2015-11-09
• [Presentation] Human iPS cell-derived 3D engineered cardiac tissue including cardiomyocytes and multiple vascular lineages for cardiac regeneration. (2015)
  • Author(s): Masumoto H, Sakata R, Yamashita JK et al.
  • Organizer: American Heart Association 2015
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Transplantation of genomic integration-free human iPS cell-derived cardiac tissue sheets into Porcine infarct hearts produced no lethal arrhythmia : A preclinical study for a safer human iPS cell therapy. (2015)
  • Author(s): Aoki T, Sakata R, Yamashita JK et al.
  • Organizer: American Heart Association 2015
  • Place of Presentation: Orlando, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] ardiac tissue sheet including human iPS cell-derived cardiomyocytes and vascular cells restores impaired left ventricular systolic function of infarcted porcine hearts: a preclinical study. (2015)
  • Author(s): Masumoto H, Sakata R, Yamashita JK et al.
  • Organizer: European Society of Cardiology (ESC) Congress
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] Development of 3D Engineered Cardiac Tissue with Human iPS Cell-derived Cardiomyocytes and Endothelial Cells. (2015)
  • Author(s): Masumoto H, Sakata R, Yamashita JK et al.
  • Organizer: Annual Meeting of International Society of Stem Cell Research (ISSCR).
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2015-06-24
  • Int'l Joint Research
• [Presentation] 多能性幹細胞による心筋再生研究の最前線 (2015)
  • Author(s): 升本 英利
  • Organizer: 第45回日本心臓血管外科学会学術総会
  • Place of Presentation: 京都
  • Year and Date: 2015-02-16 – 2015-02-18
• [Presentation] ミニブタ心筋梗塞モデルへのヒト iPS 細胞由来心臓組織シート移植は心機能を回復する (2015)
  • Author(s): 石上雅之助
  • Organizer: 第45回日本心臓血管外科学会学術総会
  • Place of Presentation: 京都
  • Year and Date: 2015-02-16 – 2015-02-18
• [Presentation] 2 型 VEGF 受容体陽性細胞純化再培養によるヒト iPS 細胞からの効率的血管内 皮細胞分化誘導 (2015)
  • Author(s): 幾野 毅
  • Organizer: 第45回日本心臓血管外科学会学術総会
  • Place of Presentation: 京都
  • Year and Date: 2015-02-16 – 2015-02-18
• [Presentation] Transplantation of cardiac cell sheet including human iPS cell-derived cardiomyocytes and vascular cells to infarcted porcine heart restores impaired left ventricular global function and dyssynchrony (2014)
  • Author(s): Ishigami M
  • Organizer: AHA2014
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] ミニブタ心筋梗塞モデルへのヒトiPS 細胞由来心臓組織シート移植による心機能回復 (2014)
  • Author(s): 石上 雅之助
  • Organizer: 第67回日本胸部外科学会定期学術集会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-09-30 – 2014-10-03
• [Presentation] 2型血管内皮細胞増殖因子受容体陽性細胞の純化再培養によるヒトiPS 細胞からの血管内皮細胞分化誘導の効率化 (2014)
  • Author(s): 幾野 毅
  • Organizer: 第67回日本胸部外科学会定期学術集会
  • Place of Presentation: 福岡市
  • Year and Date: 2014-09-30 – 2014-10-03
• [Presentation] Scalable and highly efficient endothelial cell differentiation methods from human induced pluripotent stem cells based on monolayer and serum-free culture (2014)
  • Author(s): Ikuno T
  • Organizer: ESC Congress 2014
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
• [Presentation] Scalable and highly efficient endothelial cell differentiation methods from human induced pluripotent stem cells based on monolayer and serum-free culture for realization of regenerative medicine (2014)
  • Author(s): Ikuno T
  • Organizer: International Society for Stem Cell Research (ISSCR)
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-18 – 2014-06-21
• [Presentation] High-purity and scalable endothelial cell differentiation methods from human induced pluripotent stem cells based on monolayer and serum-free culture (2014)
  • Author(s): Ikuno T
  • Organizer: 18th International Vascular Biology Meeting
  • Place of Presentation: Kyoto
  • Year and Date: 2014-04-14 – 2014-04-17
• [Presentation] CELL SHEET TRANSPLANTATION TO RAT INFARCT HEART USING GENOMIC INTEGRATION-FREE HUMAN IPS CELLS GENERATED WITH EPISOMAL PLASMID VECTORS: A STRATEGY FOR TUMOR-FREE CARDIAC CELL THERAPY (2014)
  • Author(s): Masumoto H.， Marui A.， Sakata R.， Yamashita JK. et al.
  • Organizer: ISSCR(International Society for Stem Cell Research) 12th Annual Meeting
  • Place of Presentation: Vancouver, Canada
• [Presentation] 多能性幹細胞由来心臓組織様シートの効果的積層化は移植細胞の生着効率を改善し心筋梗塞後の心機能低下を抑制する (2013)
  • Author(s): 松尾 武彦， 升本 英利， 丸井 晃， 坂田 隆造ほか
  • Organizer: 第66回日本胸部外科学会定期学術集会
  • Place of Presentation: 仙台市
• [Presentation] 再生医学研究が変える外科の近未来 細胞シート技術を用いた多能性幹細胞による心筋再生研究 機能的再生から組織再生へ (2013)
  • Author(s): 升本 英利， 丸井 晃， 山下 潤， 坂田 隆造ほか
  • Organizer: 第113回日本外科学会定期学術集会
  • Place of Presentation: 福岡市
• [Presentation] The Transplantation of Human iPS Cell-Derived Cardiac Cell Sheets to Rat Myocardial Infarction Model Ameliorates Cardiac Dysfunction Through Neovascularization． (2013)
  • Author(s): Masumoto H.， Marui A.， Sakata R.， Yamashita JK et al.
  • Organizer: The 21st Annual Meeting Of The Asian Society For Cardiovascular And Thoracic Surgery (ASCVTS2013)
  • Place of Presentation: 神戸市
• [Presentation] Transplantation of Human Induced Pluripotent Stem Cell-Engineered Tissue Sheets with Defined Cardiovascular Cell Populations for Infarcted Rat Hearts (2013)
  • Author(s): Masumoto H.， Marui A.， Sakata R.， Yamashita JK. et al.
  • Organizer: ISSCR(International Society for Stem Cell Research) 11th Annual Meeting
  • Place of Presentation: Boston, USA
• [Presentation] An efficient piling up of pluripotent stem cell-derived cardiac tissue-like sheets that robustly promotes cell engraftment and ameliorates cardiac dysfunction after myocardial infarction (2013)
  • Author(s): Matsuo T.， Masumoto H.， Marui A.， Sakata R.， Yamashita JK.et al.
  • Organizer: ESC (European Society for Cardiology) Congress2013
  • Place of Presentation: Amsterdam, Netherlands
• [Presentation] Safety and Efficacy of Sustained Release of basic fibroblast growth factor Using Biodegradable Gelatin Hydrogel in Patients With Critical Limb Ischemia (2013)
  • Author(s): Matsuo T.， Masumoto H.， Marui A.， Sakata R.， Yamashita JK.et al.
  • Organizer: AHA (American Heart Association) Scientific Sessions 2013
  • Place of Presentation: Dallas, USA
• [Book] Annual Review循環器：心筋再生医療の進歩. (2016)
  • Author(s): 升本英利、坂田隆造
  • Total Pages: 7
  • Publisher: 中外医学社
• [Book] Pluripotent Stem Cells, ISBN 978-953-51-1192-4 (2013)
  • Author(s): Masumoto H, Yamashita JK
  • Total Pages: 372
  • Publisher: InTech
• [Remarks] 京都大学 心臓血管外科
  • URL: http://kyoto-cvs.jp/