Development of electrophysiological indices to predict proarrhythmic risk of a drug in a human iPS cell-derived cardiomyocytes' sheet through its functional characterization

• Project/Area Number: 17K08608
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Toho University
• Principal Investigator: Izumi-Nakaseko Hiroko 東邦大学, 医学部, 准教授 (80408773)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ヒトiPS細胞由来心筋細胞 / 多電極システム / 催不整脈性 / 抗不整脈性 / イオンチャネル / モーションベクトル / 心毒性 / 電気生理学 / 電気薬理学 / ヒトiPS細胞 / 心筋細胞 / マルチチャネル遮断薬 / トキシコロジー / ＱＴ延長症候群 / iPS

Outline of Final Research Achievements

In this project, I developed electrophysiological indices for human iPS cell-derived cardiomyocytes’ monolayer sheets to outline the pro- and/or anti-arrhythmic properties of drugs. Each cell sheet was prepared on each microelectrode-array probe, and then paced with programmed stimuli via a pair of adjacent electrodes before and after drug treatment. I examined the electrophysiological indices of the cell sheet for detecting Na+ channel blockade with its characteristics, blockade of K+ and Ca2+ channels, and their balance in the repolarization phase using clinical antiarrhythmics. I then assessed an anticancer agent and a Kampo preparation with the indices and detected their multichannel blocking actions. The obtained results indicated that the cell sheets with the indices could be valuable to predict pro- and/or anti-arrhythmic action of a substance in the human intact heart.

Academic Significance and Societal Importance of the Research Achievements

多くの薬物が主作用の他に、心臓のイオンチャネルを修飾し、その結果、催不整脈性や抗不整脈性を持つことが明らかになっており、その作用を見極めることは大変重要である。ヒトiPS心筋細胞はヒトの生体心と同じイオンチャネルを発現しているので、この細胞を使用して催不整脈性や抗不整脈性を正確に評価できれば、種差もなく、ヒト生体心へその結果を外挿することが出来る。本研究では2 mm四方のヒトiPS細胞由来心筋細胞シートに多電極システムと電気刺激を組み合わせることにより、複数のイオンチャネル遮断作用をもつ薬物であっても催不整脈性や抗不整脈性の概要が把握できる電気生理学的指標を開発した。

Research Products

• [Journal Article] Optimizing the Direction and Order of the Motion Unveiled the Ability of Conventional Monolayers of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes to Show Frequency-Dependent Enhancement of Contraction and Relaxation Motion (2020)
  • Author(s): Izumi-Nakaseko Hiroko、Chiba Koki、Hagiwara-Nagasawa Mihoko、Satsuka Ayano、Goto Ai、Nunoi Yoshio、Kambayashi Ryuichi、Matsumoto Akio、Takei Yoshinori、Kanda Yasunari、Naito Atsuhiko T.、Sugiyama Atsushi
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 8 Pages: 542562-542562
  • DOI: 10.3389/fcell.2020.542562
  • Peer Reviewed / Open Access
• [Journal Article] Dasatinib can Impair Left Ventricular Mechanical Function But May Lack Proarrhythmic Effect: A Proposal of Non-clinical Guidance for Predicting Clinical Cardiovascular Adverse Events of Tyrosine Kinase Inhibitors. (2020)
  • Author(s): Izumi-Nakaseko H, Fujiyoshi M, Hagiwara-Nagasawa M, Goto A, Chiba K, Kambayashi R, Naito AT, Ando K, Kanda Y, Ishii I, Sugiyama A
  • Journal Title: Cardiovasc Toxicol. Volume: 20(1) Issue: 1 Pages: 58-70
  • DOI: 10.1007/s12012-019-09538-5
  • Peer Reviewed
• [Journal Article] Analysis of electro-mechanical relationship in human iPS cell-derived cardiomyocytes sheets under proarrhythmic condition assessed by simultaneous field potential and motion vector recordings. (2019)
  • Author(s): Sugiyama A, Hagiwara-Nagasawa M, Kambayashi R, Goto A, Chiba K, Naito AT, Kanda Y, Matsumoto A, Izumi-Nakaseko H
  • Journal Title: J Pharmacol Sci Volume: 140(4) Issue: 4 Pages: 317-320
  • DOI: 10.1016/j.jphs.2019.07.006
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of the drug-induced toxicity on left ventricular function by pattern-cultured hiPSC-CMs. (2019)
  • Author(s): Naito A, Ito M, Gao F, Furuya A, Izumi-Nakaseko H, Hagiwara-Nagasawa M, Sugiyama A
  • Journal Title: J Pharmacol Toxicol Methods Volume: 99 Pages: 106595-106595
  • DOI: 10.1016/j.vascn.2019.05.171
  • Peer Reviewed
• [Journal Article] Application of human induced pluripotent stem cell-derived cardiomyocytes sheets with microelectrode array system to estimate antiarrhythmic properties of multi-ion channel blockers (2018)
  • Author(s): Izumi-Nakaseko Hiroko、Hagiwara-Nagasawa Mihoko、Naito Atsuhiko T.、Goto Ai、Chiba Koki、Sekino Yuko、Kanda Yasunari、Sugiyama Atsushi
  • Journal Title: Journal of Pharmacological Sciences Volume: 137 Issue: 4 Pages: 372-378
  • DOI: 10.1016/j.jphs.2018.07.011
  • Peer Reviewed / Open Access
• [Journal Article] Development of correction formula for field potential duration of human induced pluripotent stem cell-derived cardiomyocytes sheets (2017)
  • Author(s): Izumi-Nakaseko H, Kanda Y, Nakamura Y, Hagiwara-Nagasawa M, Wada T, Ando K, Naito AT, Sekino Y, Sugiyama A
  • Journal Title: Journal of pharmacological sciences Volume: 135 Issue: 1 Pages: 44-50
  • DOI: 10.1016/j.jphs.2017.08.008
  • Peer Reviewed / Open Access
• [Presentation] 生薬甘草の心臓への電気薬理学的作用： in vitroとin vivoモデルを用いた統合的解析 (2021)
  • Author(s): 中瀬古（泉）寛子, 千葉浩輝, 後藤愛, 神林隆一, 布井啓雄, 長澤（萩原）美帆子, 松本明郎, 武井義則, 川合眞一, 杉山篤
  • Organizer: 第94回日本薬理学会年会
• [Presentation] Effects of hyperglycemia and hyperosmolarity on cardiac electrophysiology and hemodynamics in in vivo canine model (2021)
  • Author(s): Izumi-Nakaseko H, Goto A, Kambayashi R, Hirokawa Y, Hagiwara-Nagasawa M, Nunoi Y, Takei Y, Matsumoto A, Kawai S, Taubel J, Sugiyama A
  • Organizer: 第98回日本生理学会大会
• [Presentation] Development and assessment of a new in vitro platform of human induced pluripotent stem cell-derived cardiomyocytes for evaluating the drug-induced biological phenomena predicting clinically observed cardiac effects. (2020)
  • Author(s): Izumi-Nakaseko H, Chiba K, Hagiwara-Nagasawa M, Goto A, Nunoi Y, Kambayashi R, Matsumoto A, Kanda Y, Naito AT, Sugiyama A
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Physiological properties of excitation-contraction relationships in human induced pluripotent stem cell-derived cardiomyocytes sheets. (2020)
  • Author(s): Izumi-Nakaseko H, Chiba K, Hagiwara-Nagasawa M, Goto A, Nunoi Y, Kambayashi R, Matsumoto A, Kanda Y, Naito AT, Sugiyama A
  • Organizer: 第97回日本生理学会大会
• [Presentation] チロシンキナーゼ阻害薬のヒト心血管有害作用を予測する非臨床的評価方法の開発 (2019)
  • Author(s): 中瀬古（泉）寛子, 藤吉正哉, 長澤（萩原）美帆子, 安東賢太郎, 内藤篤彦, 石井伊都子, 杉山篤
  • Organizer: 第4回J-ISCP年次学術集会（国際心血管薬物療法学会日本部会）
• [Presentation] 抗がん薬の心血管有害作用検出のための非臨床的評価プロトコルの提案 (2019)
  • Author(s): 中瀬古(泉)寛子, 杉山篤
  • Organizer: 第2回日本腫瘍循環器学会学術集会
  • Invited
• [Presentation] ダサチニブは左心機能を低下するが、催不整脈作用を示さない：チロシンキナーゼ阻害薬のヒト心血管有害作用を予測する非臨床的評価方法の開発 (2019)
  • Author(s): 中瀬古（泉）寛子, 藤吉正哉, 長澤（萩原）美帆子, 後藤愛, 千葉浩輝, 神林隆一, 内藤篤彦, 安東賢太郎, 諫田泰成, 石井伊都子, 杉山篤
  • Organizer: 第141回日本薬理学会関東部会
• [Presentation] Electrophysiological analyses of multi-ion channel blockers in hiPSC-CMs sheets with MEA system (2019)
  • Author(s): Izumi-Nakaseko H, Naito AT, Sekino Y, Hagiwara-Nagasawa M, Goto A, Chiba K, Kanda Y, Sugiyama A
  • Organizer: 9th FAOPS Congress(Kobe, Japan)
  • Int'l Joint Research
• [Presentation] ダサチニブは左室機能を抑制する一方、催不整脈性はない：in vivoとin vitro実験系の併用研究 (2019)
  • Author(s): 中瀬古（泉）寛子, 石井伊都子, 藤吉正哉, 長澤（萩原）美帆子, 安東賢太郎, 内藤篤彦, 杉山篤
  • Organizer: 第10回日本安全性薬理研究会(東京, 日本)
• [Presentation] ヒトiPS由来心筋細胞と多電極システムを用いた多チャネル遮断薬の電気薬理学的作用の検出 (2019)
  • Author(s): 中瀬古（泉）寛子, 長澤（萩原）美帆子, 内藤篤彦, 後藤愛, 千葉浩輝, 関野祐子, 諫田泰成, 杉山篤
  • Organizer: 第92回日本薬理学会年会(大阪, 日本)
• [Presentation] Assessment of the drug-induced cardiac functional toxicity by pattern-cultured hiPSC-CMs. (2018)
  • Author(s): Naito AT, Ito M, Izumi-Nakaseko H, Ando K, Hagiwara-Nagasawa M, Nakamura Y, Sugiyama A
  • Organizer: WCP2018(Kyoto)
  • Int'l Joint Research
• [Presentation] Development of correction formula for frequency-dependent changes of field potential duration of human induced pluripotent stem cell-derived cardiomyocytes sheets. (2018)
  • Author(s): Izumi-Nakaseko H, Kanda Y, Nakamura Y, Hagiwara-Nagasawa M, Ando K, Naito AT, Sekino Y, Sugiyama A
  • Organizer: WCP2018(Kyoto)
  • Int'l Joint Research
• [Presentation] モンゴル薬用植物Adonis mongolicaの心血管系に対する薬理作用 (2018)
  • Author(s): 中瀬古（泉）寛子, 李巍, 長澤（萩原）美帆子, 田中耕一郎 , Choijamts G, Batkhuyag P, Yeruult C, Khaliun N, Narantungalag D, 内藤篤彦, 小池一男, 杉山篤
  • Organizer: 第20回応用薬理シンポジウム(東京)
• [Presentation] ヒト人工多能性幹細胞由来心筋細胞シートの細胞外電位持続時間の補正式の開発 (2018)
  • Author(s): 中瀬古（泉）寛子, 諫田泰成, 長澤（萩原）美帆子, 内藤篤彦, 関野祐子, 杉山篤
  • Organizer: 第20回応用薬理シンポジウム(東京)
• [Presentation] Assessment of the drug-induced toxicity against left ventricular function by pattern-cultured hiPSC-CMs. (2018)
  • Author(s): Naito AT, Ito M, Gao FY, Furuya A, Izumi-Nakaseko H, Mihoko Hagiwara-Nagasawa M, Sugiyama A
  • Organizer: Safety Pharmacology Science Annual Meeting(Washington DC, USA)
  • Int'l Joint Research
• [Presentation] がん分子標的薬dasatinibの心毒性の定量評価 (2018)
  • Author(s): 中瀬古（泉）寛子, 石井伊都子, 藤吉正哉, 長澤（萩原）美帆子, 安東賢太郎, 内藤篤彦, 杉山 篤
  • Organizer: ダイバーシティ研究環境実現イニシアティブ 共同研究推進のためのセミナー＆研究発表会(千葉)
• [Presentation] ヒトiPS細胞由来心筋細胞シートを用いたマルチチャネル遮断薬の抗不整脈作用の評価 (2018)
  • Author(s): 中瀬古（泉）寛子, 長澤（萩原）美帆子, 内藤篤彦, 後藤愛, 千葉浩輝, 関野祐子, 諫田泰成, 杉山篤
  • Organizer: 第28回日本循環薬理学会(東京)
• [Presentation] Electrophysiological characterization of the field potential duration in human induced pluripotent stem cell-derived cardiomyocytes sheets (2018)
  • Author(s): Izumi-Nakaseko H, Kanda Y, Nakamura Y, Hagiwara-Nagasawa M, Wada T, Ando K, Naito AT, Sekino Y, Sugiyama A
  • Organizer: 第95回日本生理学会大会
• [Presentation] Characterization of frequent-dependent changes of field potential duration in human induced pluripotent stem cell-derived cardiomyocytes sheets (2017)
  • Author(s): Izumi-Nakaseko H, Kanda Y, Nakamura Y, Hagiwara-Nagasawa M, Wada T, Ando K, Naito AT, Sekino Y, Sugiyama A
  • Organizer: 第27回日本循環薬理学会
• [Presentation] Development of correction formula for field potential duration of human induced pluripotent stem cell-derived cardiomyocytes sheets. (2017)
  • Author(s): Izumi-Nakaseko H, Kanda Y, Nakamura Y, Hagiwara-Nagasawa M, Wada T, Ando K, Naito AT, Sekino Y, Sugiyama A
  • Organizer: 第64回日本不整脈心電学会学術大会
  • Int'l Joint Research