Identification of the mechanisms for hereditary arrhythmic disease using human iPS cell technology

• Project/Area Number: 25461117
• 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: Murata Mitsushige 慶應義塾大学, 医学部, 講師 (30317135)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: 心臓 / 再生医療 / 不整脈 / イオンチャネル / iPS細胞 / 心筋細胞

Outline of Final Research Achievements

We have previously reported that human induced pluripotent stem (iPS) cell technology is useful for disease specific in vivo cell model and drug screening. Since many kinds of ion channels express in the cardiomyocytes, it is desirable to investigate the effects of anti-arrhythmic drugs on electrophysiological properties in native cardiomyocytes.
In this study, first, we have succeeded in the induction of human iPS cell derived cardiomyocytes. QT PCR analyses revealed the expression of several ion channels such as SCN5A、CACNA1G、HCN4 in undifferentiated human iPS cells. Second, we investigated the effects of Bepridil on ion channel expression in human iPS cell derived cardiomyocytes. Bepridil dose dependently increased the expression of SCN5A, CACNA1, CACNA1G, HCN4. These results indicated that Bepridil may modulate ion channel expression in cardiomyocytes, resulting in the chronic effects of Bepridil in addition to the acute direct effect on the ion channels.

Research Products

• [Journal Article] Significance of Echocardiographic Assessment for Right Ventricular Function after Balloon Pulmonary Angioplasty in Patients with Chronic Thromboembolic Induced Pulmonary Hypertension (2015)
  • Author(s): Tsugu T, Murata M, Kawakami T, Yasuda R, Tokuda H, Minakata Y, Tamura Y, Kataoka M, Hayashida K, Tsuruta H, Maekawa Y, Inoue S, Fukuda K
  • Journal Title: Am J Cardiol Volume: 115 Issue: 2 Pages: 256-261
  • DOI: 10.1016/j.amjcard.2014.10.034
  • Peer Reviewed
• [Journal Article] Generation and characterization of functional cardiomyocytes derived from human T cell-derived induced pluripotent stem cells. (2014)
  • Author(s): Seki T, Yuasa S, Kusumoto D. Tohyama S, et al.
  • Journal Title: PLoS One. Volume: 9 Issue: 1 Pages: 1-7
  • DOI: 10.1371/journal.pone.0085645
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of Rad leads to arrhythmogenesis via PKA-mediated upregulation of Ryanodine receptor activity in the heart. (2014)
  • Author(s): Yamakawa H, Murata M, Suzuki T, Yada H, Ishida H, Aizawa Y, Adachi T, Kamiya K, Fukuda K.
  • Journal Title: Biochem Biophys Res Commun Volume: 452 Issue: 3 Pages: 701-707
  • DOI: 10.1016/j.bbrc.2014.08.126
  • Peer Reviewed / Open Access
• [Journal Article] Distinct Metabolic Flow Enable Large-Scale Purification of Mouse and Human Pluripotent Stem Cell-Derived Cardiomyocytes. (2013)
  • Author(s): Tohyama S, Hattori F, Sano M, et al.
  • Journal Title: Cell Stem Cell Volume: 12 Issue: 1 Pages: 127-37
  • DOI: 10.1016/j.stem.2012.09.013
  • Peer Reviewed
• [Journal Article] Brugada syndrome behind complete right bundle-branch blosk (2013)
  • Author(s): Aizawa Y, Takatsuki S, Sano M, Kimura T, Nishiyama N, Fukumoto K, Tanimoto Y, Tanimoto K, Murata M, Komatsu T, Mitamura H, Ogawa S, Funazaki T, Sato M, Aizawa Y, Fukuda K
  • Journal Title: Circulation Volume: 128 Issue: 10 Pages: 1048-1054
  • DOI: 10.1161/circulationaha.113.003472
  • Peer Reviewed
• [Journal Article] Diagnostic value of portable electrocardiogram (Cardiophone) in patients complaining of palpitation (2013)
  • Author(s): Aizawa Y, Takatsuki S, Suenaga Y, Kimura T, Nishiyama N, Fukumoto K, Tanimoto Y, Tanimoto K, Kohsaka S, Fukuda Y, Murata M, Miyoshi S, Sato T, Iwanaga S, Ogawa S, Fukuda K
  • Journal Title: International Journal of Cardiolgy Volume: 168 Issue: 3 Pages: 2925-2927
  • DOI: 10.1016/j.ijcard.2013.03.182
  • Peer Reviewed
• [Journal Article] Distinct iPS Cells shows different Cardiac Differentiation Efficiency. (2013)
  • Author(s): Ohno Y, Yuasa S, Seki T, Fukuda K., et al.
  • Journal Title: Stem Cells International Volume: 2013 Pages: 659739-659739
  • DOI: 10.1155/2013/659739
  • Peer Reviewed
• [Presentation] Echocardiographic evaluation of the mechanisms for right ventricular dysfunction in chronic thromboembolic pulmonary hypertension (2015)
  • Author(s): 39.Tsugu T, Murata M, Kawakami T, Tokuda H, Minakata Y, Kataoka M, Tsuruta H, Itabashi Y, Kanazawa H, Mahara K, Fukuda K
  • Organizer: 88th American Heart Association scientific meeting
  • Place of Presentation: Orland, USA
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] RV dyssynchrony predicts clinical outcomes after balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension (2015)
  • Author(s): 38.Tsugu T, Murata M, Kawakami T, Tokuda H, Minakata Y, Kataoka M, Tsuruta H, Itabashi Y, Kanazawa H, Fukuda K
  • Organizer: European Society of Cardiology annual meeting
  • Place of Presentation: London, UK
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] Pathophysiological analysis of the hereditary heart disease using iPS cells (2015)
  • Author(s): 153.Kuroda Y, Yuasa S, Watanabe Y, Hattori T, Ohno S, Egashira T, Seki T, Okata S, Tanaka A, Aizawa Y, Suzuki T, Murata M, Aiba T, Makita N, Shimizu W, Kodama I, Horie M, Horigome H, Kamiya K, Fukuda K.
  • Organizer: 第79回日本循環器学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2015-04-24
• [Presentation] Uncovering the Pathophysiology of Short-coupled Variant of Torsade de Pointes by Disease Specific-induced Pluripotent Stem Cells (2014)
  • Author(s): Suzuki T, Yuasa S, Takei M, Murata M, Kamiya K, Fukuda K
  • Organizer: 第７8回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] Disease Modeling for Andersen-Tawil Syndrome Using Patient-Specific iPS Cell (2014)
  • Author(s): Kuroda Y, Yuasa S, Hattori T, egashira T, Aizawa Y, Seki T, Murata M, Okata S, Ohno S, Horie M, Fukuda K, Kamiya K
  • Organizer: 第７8回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] Disease Modeling Using iPS Cells (2014)
  • Author(s): Furukawa T, Okata S, Yuasa S, Suzuki T, Makita N, Kurokawa J, Egashira T, Yamakawa H, Seki T, Aizawa T, Hashimoto H, Kudoda Y, Tanaka A, Yae K, Murata M, Aiba T, Shimizu W, Horie M, Kodama I, Ogawa S, Fukuda K
  • Organizer: 第７8回日本循環器学会学術集会
  • Place of Presentation: 東京
• [Presentation] Clinical applications of tissue imaging for specific cases (2013)
  • Author(s): Murata M
  • Organizer: 2013 American Society of Echocardiography Annual Scientific Meeting
  • Place of Presentation: Minneapolis
  • Invited