Development of human iPS cell-derived multidisciplinary thick viable organized tissues aiming for myocardial regenerative therapy

• Project/Area Number: 15K10210
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular surgery
• Research Institution: Kyoto University
• Principal Investigator: Nakata Tomohiro 京都大学, 医学研究科, 助教 (00559685)
• Co-Investigator(Kenkyū-buntansha): 池田 義 京都大学, 医学研究科, 准教授 (40281092) ; 田畑 泰彦 京都大学, ウイルス・再生医科学研究所, 教授 (50211371)
• Co-Investigator(Renkei-kenkyūsha): YAMASHITA JUN 京都大学, その他部局等, 教授 (50335288)
• Research Collaborator: MASUMOTO HIDETOSHI 京都大学, 大学院医学研究科, 特定助教 (70645754)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: iPS細胞 / バイオエンジニアリング / 心臓再生 / 心筋疾患外科学 / 拡張型心筋症 / バイトエンジニアリング

Outline of Final Research Achievements

We established a technology to generate human iPS cell-derived thick viable cardiac tissues. We validated the therapeutic potential of the tissues for porcine sub-acute myocardial infarction model, rat chronic myocardial infarction model and hamster dilated cardiomyopathy modei. Histological studies revealed the therapeutic mechanisms including the attenuation of fibrosis, angiogenesis, the attenuation of apoptosis and cardiomyocyte hypertrophy. We also established the method to generate cardiac tissue sheets and thick viable tissues from clinical-graded stock human iPS cells from Center for iPS cell Research and Application, Kyoto University. There results including the validation of the therapeutic effects of the bioengineeded tissue and the therapeutic mechanism would serve as a basis for iPS cell-based cardiac regenerative therapy.

Research Products

• [Journal Article] Impact of Cell Composition and Geometry on Human Induced Pluripotent Stem Cells-Derived Engineered Cardiac Tissue. (2017)
  • Author(s): Nakane T, Masumoto H, Tinney JP, Yuan F, Kowalski WJ, Ye F, LeBlanc AJ, Sakata R, Yamashita JK, Keller BB.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 45641-45641
  • DOI: 10.1038/srep45641
  • NAID: 120006309290
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fetal mesenchymal stem cells ameliorate acute lung injury in a rat cardiopulmonary bypass model. (2017)
  • Author(s): 7.Taki T, Masumoto H, Funamoto M, Minakata K, Yamazaki K, Ikeda T, Sakata R.
  • Journal Title: The Journal of Thoracic and Cardiovascular Surgery Volume: 153 Issue: 3 Pages: 726-734
  • DOI: 10.1016/j.jtcvs.2016.10.014
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Prevention of abdominal aortic aneurysm progression by oral administration of green tea polyphenol in a rat model. (2016)
  • Author(s): Setozaki S, Minakata K, Masumoto H, Hirao S, Yamazaki K, Kuwahara K, Ikeda T, Sakata R.
  • Journal Title: J Thorac Cardiovasc Surg. Volume: - Issue: 6 Pages: 1803-1812
  • DOI: 10.1016/j.jvs.2016.06.003
  • Peer Reviewed / Acknowledgement Compliant
• [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
• [Presentation] Mesh-shaped engineered cardiac tissue generated from human iPS cell for cardiac regeneration (2017)
  • Author(s): Nakane T, Masumoto H, Minakata K, Ikeda T, Minatoya K, Yamashita J, Sakata R
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢市
  • Year and Date: 2017-03-17
  • Int'l Joint Research
• [Presentation] Transplantation of human induced pluripotent stem cell-derived cardiac tissue ameliorates heart failure in delated cardiomyopathy of hamster model (2017)
  • Author(s): 瀧本 真也，升本 英利，南方 謙二，池田 義，湊谷 謙司，坂田 隆造，山下 潤
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢市
  • Year and Date: 2017-03-17
  • Int'l Joint Research
• [Presentation] Spring-8における位相差CTによる拡張型心筋症ハムスターに対する立体的組織評価の確立 (2017)
  • Author(s): 平尾 慎吾，南方 謙司，升本 英利，瀧本 真也，坂本 和久，中津 太郎，中田 朋宏，山﨑 和裕，池田 義，湊谷 謙司，坂田 隆造
  • Organizer: 第47回日本心臓血管外科学会学術総会
  • Place of Presentation: 東京都
  • Year and Date: 2017-02-27
  • Int'l Joint Research
• [Presentation] 慢性期ラット心筋梗塞に対するbFGF徐放後ヒトiPS由来心筋組織シート移植の治療効果 (2017)
  • Author(s): 李 子澎，升本 英利，南方 謙二，川東 正英，瀧本 真也，平尾 慎吾，池田 義，坂田 隆造，湊谷 謙司
  • Organizer: 第47回日本心臓血管外科学会学術総会
  • Place of Presentation: 東京都
  • Year and Date: 2017-02-27
  • Int'l Joint Research
• [Presentation] 拡張型心筋症ハムスターに対するヒトiPS細胞由来心臓組織シート移植の有効性 (2017)
  • Author(s): 瀧本 真也，升本 英利，南方 謙二，池田 義，湊谷 謙司
  • Organizer: 第47回日本心臓血管外科学会学術総会
  • Place of Presentation: 東京都
  • Year and Date: 2017-02-27
  • Int'l Joint Research
• [Presentation] ヒトiPS細胞由来心筋・血管系細胞を用いた移植用網目状心臓組織パッチの開発 (2017)
  • Author(s): 中根 武一郎，升本 英利，南方 謙二，池田 義、湊谷 謙司
  • Organizer: 第47回日本心臓血管外科学会学術総会
  • Place of Presentation: 東京都
  • Year and Date: 2017-02-27
  • Int'l Joint Research
• [Presentation] Three-dimensional visualization and morphometry of cardidac tissue in a hamster DCM model by synchrotron radiation-based x-ray phasecontrast imaging at SPring-8 (2017)
  • Author(s): Hirao S, Minakata K, Masumoto H, Takimoto S, Hoshino M, Yagi N, Shirai M, Minatoya K, Sakata R
  • Organizer: 第81回日本循環器学会学術集会
• [Presentation] Three-dimenshional visualization and morphometry of caediac tiddue in a hamster DCM model by synchrotron radiation-based X-ray phase-contrast imaging at Spring-8 (2017)
  • Author(s): Hirao S, Masumoto H, Hoshino M, Minakata K, Takimoto S, Ikeda T, Yamashita J.K, Yagi N, Minatoya K.
  • Organizer: European Society of Cardiology Congress 2017
  • Int'l Joint Research
• [Presentation] Three-dimensional Visualization and Morphometry of Cardiac Tissue in a Hamster DCM Model by Synchrotron Radiation-based X-ray Phase-contrast Imaging at Spring-8 (2017)
  • Author(s): Hirao S, Masumoto H, Hoshino M, Kanemitsu H, Ueyama K, Yamazaki K, Ikeda T, Yamashita J.K, Yagi N, Minatoya K
  • Organizer: American Heart Association 2017
  • Int'l Joint Research
• [Presentation] The therapeutic potential of human iPS cell-derived cardiac tissue onto a porcine myocardial infarction model. (2017)
  • Author(s): Hirao S, Masumoto H, Nishio H, Kawatou M, Li Z, Kanemtitsu H, Ueyama K,Yamazaki K,Ikeda T,Tabata Y, Yamashita J.K, Minatoya K.
  • Organizer: American Heart Association 2017
  • Int'l Joint Research
• [Presentation] ヒトiPS細胞由来心筋・血管系細胞を用いた移植用網目状心臓組織パッチの開発 (2017)
  • Author(s): 中根 武一郎，升本 英利，池田 義，湊谷 謙司，山下 潤，Bradley B.Keller
  • Organizer: 第16回日本心臓血管外科再生治療研究会
  • Place of Presentation: 東京都
  • Int'l Joint Research
• [Presentation] Impact of geometry and cell density on structural and functional maturation in large-format mesh engineered cardiac tissues (2016)
  • Author(s): Nakane T, Masumoto H, J P. Tinney, F Yuan, W J. Kowalski, F Ye, Minakata K, Ikeda T, Sakata R, Yamashita J.K, B B.Keller
  • Organizer: AHA American Heart Association
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Sequential treatment with sustained-release of basic fibroblast growth factor followed by transplantation of human induced pluripotent stem cell-derived cardiac tissue improved left ventricular function in a rat chronic myocardial infarction model (2016)
  • Author(s): Zipeng Li, Masumoto H, Minakata K, Kawatou M, Takimoto S, Hirao S, Ikeda T, Tabata Y, Yamashita J.K, Sakata R
  • Organizer: AHA American Heart Association
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] A technology for cardiac regeneration using human iPS cell-derived cardiac tissue including multiple cardiovascular lineages (2016)
  • Author(s): Masumoto H, Yamamizu K, Ikuno T, Takakubo H, Minakata K, Ikeda T, Tabata Y, Yamashita J.K.
  • Organizer: AHA American Heart Association
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] The efficacy of transplantation of human iPS cell derived cardiac tissue for dilated cardiomyopathy hamster model (2016)
  • Author(s): Takimoto S, Masumoto H, Minakata K, Tabata Y, Yamashita J.K.
  • Organizer: AHA American Heart Association
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] ヒトiPS細胞由来心筋細胞および血管構成細胞を含む三次元人工心筋組織による心筋再生についての検討 (2016)
  • Author(s): 升本 英利，中根 武一郎，南方 謙二，池田 義，坂田 隆造
  • Organizer: 第69回日本胸部外科学会定期学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2016-09-28
• [Presentation] 拡張型心筋症ハムスターに対するヒトiPS細胞由来心臓組織シート移植の有効性 (2016)
  • Author(s): 瀧本 真也，升本 英利，南方 謙二，池田 義，坂田 隆造
  • Organizer: 第69回日本胸部外科学会定期学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2016-09-28
• [Presentation] ヒトiPS細胞由来心筋・血管系細胞を用いた移植用大型心臓パッチの開発 (2016)
  • Author(s): 中根 武一郎，升本 英利，南方 謙二，池田 義，坂田 隆造
  • Organizer: 第69回日本胸部外科学会定期学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2016-09-28
• [Presentation] Combined transplantation of human iPS cell-derived cardiac tissue sheets and sustained-release of bFGF improved left ventricular function in a rat chronic myocardial infarction model (2016)
  • Author(s): 李 子澎，升本 英利，南方 謙二，川東 正英，瀧本 真也，平間 大介，平尾 慎吾，池田 義，坂田 隆造
  • Organizer: 第69回日本胸部外科学会定期学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2016-09-28
• [Presentation] 心臓血管領域における再生治療の展望 (2016)
  • Author(s): 南方 謙二，升本 英利，池田 義
  • Organizer: 第37回日本炎症・再生医学会
  • Place of Presentation: 京都市
  • Year and Date: 2016-06-16
• [Presentation] Cardiac 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, Ishigami M, Aoki T, Takai F, Ikuno T, Kawatoh M, Minakata K, Ikeda T, Sakata R, Yamashita JK.
  • Organizer: European Society of Cardiology (ESC) Congress
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Remarks] 京都大学 心臓血管外科