Generation and mechanism identification of mature chamber-specific cardiomyocytes derived from human induced pluripotent stem cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16041
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 43010:Molecular biology-related
• Research Institution: Kyoto University
• Principal Investigator: Koakutsu Misato 京都大学, iPS細胞研究所, 特定研究員 (90565813)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: hiPS細胞由来心筋細胞 / 心室筋細胞 / 心房筋細胞 / 成熟化

Outline of Final Research Achievements

Our research aims to generate mature cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) and identify the mechanism of cardiac maturation. To this end, we generated reporter hiPSC lines to detect gene A expression of gene A that is expressed high level in adult heart tissue but not in the fetal heart. Using CMs derived from reporter hiPSCs, we performed screening with a chemical library containing about 6600 compounds and identified compound X upregulating gene A expression. Compound X-treated hiPSC-CMs showed gene expression patterns similar to those in cardiac maturation, and also, calcium store ability in the sarcoplasmic reticulum was higher than in control CMs. Furthermore, we identified the novel maturation mechanism via regulation of neural transmitter receptor activity by compound X.

Free Research Field

幹細胞生物学

Academic Significance and Societal Importance of the Research Achievements

ヒトiPS細胞由来心筋細胞(hiPSC-CMs)は薬剤開発に有用な疾患モデル細胞の作製や再生医療への応用が期待されているが、成人の細胞と比較して成熟度が低く、機能、構造面で大きな乖離があるのが現状である。我々は化合物ライブラリーの中からhiPSC-CMsの成熟度を亢進する化合物を見出した。この化合物を数日間細胞に添加することで、心室筋細胞、心房筋細胞における遺伝子レベルでの成熟度の上昇と、心筋細胞の収縮に重要なCa2+の細胞内濃度の調節能の向上が確認された。また、化合物は神経伝達物質受容体を介して成熟化を誘導していることを明らかにするなど今後の成熟化心筋細胞作製に重要な知見を得た。