The making of the pacemaker cell by the direct cardiac reprogramming and in vivo transformation

• Project/Area Number: 15K09147
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Keio University
• Principal Investigator: YAMAKAWA Hiroyuki 慶應義塾大学, 医学部(信濃町), 客員講師 (80465020)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 再生医療 / 心筋直接誘導 / ダイレクトリプログラミング / 心筋再生 / 直接リプログラミング / 心筋転写因子 / 生体内リプログラミング / iPS細胞 / 線維芽細胞 / 繊維芽細胞

Outline of Final Research Achievements

By the in vivo reprogramming,Miyamoto et al, who was our collaborators, developed the Sendai virus vector which developed three cardiac-specific genes at the same time. Using these cariacrecprogramming Sendai virus vectors, We succeeded in making cardiac-like cells(induced cardiomyocytes: iCMs) without the genomic damage from a mouse and a human fibroblast directly efficiently in a short term on a culture dish. Furthermore, iCM reproduction began in one week when I introduced cardiomyocytes instruction Sendai virus vector into the heart of the mouse myocardial infarction model and confirmed that cardiac function was improved one month later.

Academic Significance and Societal Importance of the Research Achievements

宮本らの研究で、センダイウイルスを使用することで実現できることは示唆できた。この成果は、iPS細胞から誘導した心筋治療以外の新しい治療法を示唆できた。この成果は、社会的に大きいと考える。さらに、心筋細胞は、色々な細胞が存在していう。具体的には、右心室、左心室、ペースメーカー細胞などがあり、更に分化した心筋細胞での直接心筋誘導の研究を進める必要がある。

Research Products

• [Journal Article] Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming (2019)
  • Author(s): Muraoka Naoto、Nara Kaori、Tamura Fumiya、Kojima Hidenori、Yamakawa Hiroyuki、Sadahiro Taketaro、Miyamoto Kazutaka、Isomi Mari、Haginiwa Sho、Tani Hidenori、Kurotsu Shota、Osakabe Rina、Torii Satoru、Shimizu Shigeomi、Okano Hideyuki、Sugimoto Yukihiko、Fukuda Keiichi、Ieda Masaki
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 674-674
  • DOI: 10.1038/s41467-019-08626-y
  • NAID: 120007128245
  • Peer Reviewed / Open Access
• [Journal Article] Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction. (2018)
  • Author(s): Miyamoto K, Akiyama M, Tamura F, Isomi M, Yamakawa H, Sadahiro T, Muraoka N, Kojima H, Haginiwa S, Kurotsu S, Tani H, Wang L, Qian L, Inoue M, Ide Y, Kurokawa J, Yamamoto T, Seki T, Aeba R, Yamagishi H, Fukuda K, Ieda M.
  • Journal Title: Cell Stem Cell. Volume: 4 Issue: 1 Pages: 91-103
  • DOI: 10.1016/j.stem.2017.11.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Single-Construct Polycistronic Doxycycline-Inducible Vectors Improve Direct Cardiac Reprogramming and Can Be Used to Identify the Critical Timing of Transgene Expression. (2017)
  • Author(s): Umei TC, Yamakawa H, Muraoka N, Sadahiro T, Isomi M, Haginiwa S, Kojima H, Kurotsu S, Tamura F, Osakabe R, Tani H, Nara K, Miyoshi H, Fukuda K, Ieda M.
  • Journal Title: Int J Mol Sci. Volume: 18 Issue: 8 Pages: 1805-1805
  • DOI: 10.3390/ijms18081805
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comment on: Expandable cardiovascular progenitor cells reprogrammed from fibroblasts. (2016)
  • Author(s): Yamakawa H, Fukuda K.
  • Journal Title: Stem Cell Investig. Volume: - Pages: 89-89
  • DOI: 10.21037/sci.2016.11.07
  • Peer Reviewed / Open Access
• [Journal Article] Strategies for heart regeneration: approaches ranging from induced pluripotent stem cells to direct cardiac reprogramming. (2015)
  • Author(s): Yamakawa H, Ieda M.
  • Journal Title: Int Heart J Volume: 56 Issue: 6 Pages: 1-5
  • DOI: 10.1016/j.stemcr.2015.10.019
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Strategies for Heart Regeneration (2015)
  • Author(s): Yamakawa H, Ieda M
  • Journal Title: International Heart Journal Volume: 56 Issue: 1 Pages: 1-5
  • DOI: 10.1536/ihj.14-344
  • NAID: 130004941301
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Fabry disease has been found by using of the tumor mutational burden analysis of 3000 Japanese cancer genimis using whole genome exome and targeted gene panel seqencing:Project Hightech Omics-based Patient Evaluation (Project HOPE) (2019)
  • Author(s): Hiroyuki YAMAKAWA
  • Organizer: WORLDSymposim 2019
  • Int'l Joint Research
• [Presentation] FGF2/FGF10/VEGFが、心筋直接フル・リプログラミングを効率的に誘導する (2016)
  • Author(s): 山川裕之
  • Organizer: 第15回 再生医療学会
  • Place of Presentation: 大阪国際会議 （大阪府大阪市北区）
  • Year and Date: 2016-03-17
  • Int'l Joint Research
• [Presentation] 増殖因子による心筋リプログラミングの促進と分子機構の解明 (2016)
  • Author(s): 山川裕之
  • Organizer: 第15回 再生医療学会
  • Place of Presentation: 大阪国際会議 （大阪府大阪市北区）
  • Year and Date: 2016-03-17
  • Int'l Joint Research / Invited
• [Presentation] 特定の化合物が、心筋直接フル･リプログラミングを促進する (2015)
  • Author(s): 山川裕之
  • Organizer: 第36回 日本炎症・再生医学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京都港区）
  • Year and Date: 2015-07-23
  • Int'l Joint Research
• [Presentation] Chemical Compounds Greatly Increase Direct Cardiac Reprogramming under Defined Conditions (2015)
  • Author(s): 山川裕之
  • Organizer: 第79回 日本循環器学会
  • Place of Presentation: 大阪国際会議 （大阪府大阪市北区）
  • Year and Date: 2015-04-24
  • Int'l Joint Research