Analysis of novel genes involved in cardiac function using iPSC-derived cardiomyocytes

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08551
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Osaka Medical College
• Principal Investigator: Wakabayashi Shigeo 大阪医科大学, 医学部, 非常勤講師 (70158583)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: iPS細胞 / Na+/H+交換輸送体 / NHE1 / rhoキナーゼ / 細胞死 / 細胞運動 / ネクロ―シス / 細胞内pH

Outline of Final Research Achievements

Induced pluripotent stem cells (iPSCs) are expected in the field of the regenerative medicine from the point of view which can differentiate into cells of all organs. However, after making them differentiate, there is a serious possibility that undifferentiated remaining iPSCs become cancer. In this research, we found that overexpression of the plasma membrane Na+/H+ exchanger (NHE1) induces the cell death of iPSCs. We found that cell death occurs through strong activation of rho kinase ROCK caused by a local intracellular pH rise triggered by NHE1. Analogy to this, we also found that Na+-ionophore monensin which is a small compound with similar function as NHE1, specifically killed iPSCs. This study provides a new simple procedure through which to eliminate the iPSCs that remain after differentiation.

Free Research Field

分子細胞生理学

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、学術的には大変意義のある研究である。①細胞骨格の維持や細胞の収縮に関与するとして知られるrhoキナーゼ、ROCKが従来考えられていなかった”細胞内pHの上昇”という新しいシグナルによって活性化されること、②また、その現象が未分化なiPSCsでのみ起こり、その細胞死をもたらすことが明らかになった。社会的には、iPSCsを再生医療へ応用する際、分化せずに残ってしまうiPSCsがガン化してしまうという危険性があった。本研究で、NHE1と同様な機能を持つ低分子モネンシンはiPSCs特異的に死滅させることが判明し、簡単な操作でiPSCsを死滅除去できる方法論へと応用可能である。