1-P-066
臨床的に観察された心臓への影響を予測する薬物誘発性の生物学的現象を評価するためのヒトiPS細胞由来心筋細胞の新規in vitroプラットフォームの開発と評価
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
〇中瀬古(泉) 寛子1,2、千葉 浩輝2、長澤(萩原) 美帆子1、後藤 愛2、布井 啓雄1、神林 隆一1、松本 明郎3、諫田 泰成4、内藤 篤彦5、杉山 篤1,2,3
Hiroko Izumi-Nakaseko1,2, Koki Chiba2, Mihoko Hagiwara-Nagasawa1, Ai Goto2, Yoshio Nunoi1, Ryuichi Kambayashi1, Akio Matsumoto3, Yasunari Kanda4, T. Atsuhiko Naito5, Atsushi Sugiyama1,2,3
1東邦大・医・薬理、2東邦大・院医、3東邦大・医・加齢薬理、4国立衛研・薬理、5東邦大・医・生理
1Dept. Pharmacol., Faculty Med., Toho Univ., 2Dept. Pharmacol., Grad. Sch. Med., Toho Univ., 3Dept. Aging Pharmacol., Faculty Med., Toho Univ., 4Div. Pharmacol., NIHS., 5Dept. Physiol., Div. Cell Physiol., Toho Univ. Sch. Med.
Currently available human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been known to exert a negative force-frequency relationship as one of their immature properties. In this study, we examined whether controlling the direction of contraction process and/or supplying the higher oxygen tension may overcome such limitation of the contraction movement. We prepared one layered, higher cell-density sheets of hiPSC-CMs, and simultaneously recorded the motion vectors and field potentials. In a cell sheet under spontaneous activity, a synchronous movement consisted of multiple contractions which started from various sites. During electrical stimulation, the contraction started around the pacing electrodes and we observed the positive force-frequency relationships in contraction as well as relaxation along with the frequency-dependent shortening of the field potential durations. The use of fractional analysis of motion vectors demonstrated that contraction as well as relaxation processes consisted of fast and slow phases. Increase in oxygen tension from 20 to 95% in mixed gas accelerated the fast phase of relaxation. β-Stimulation accelerated the timing of fast phase of relaxation, whereas a tyrosine kinase inhibitor dasatinib delayed it. Thus, these observations can indicate that the currently proposed procedure may become a new tool for integrating the drug-induced biological phenomena in vitro extrapolating to clinically observed cardiac efficacy and adverse effects.