Aligned iPSC-derived cardiomyocytes enhance maturation and are useful system for drug evaluation

Abstract

Human iPSC-derived cardiomyocytes are widely used in pharmaceutical research and drug development. However, the iPSC-derived cardiomyocytes have several problems in terms of mitochondrial quantity and methods in measuring contraction compared with primary cardiomyocytes. We examined whether there was an increase in the maturation function in aligned iPSC-derived cardiomyocytes and whether they are useful for drug effects assessment.

[Method] We compared maturation motor activity responses of two kinds of iPSC-derived cardiomyocytes (iCellCM2) that were cultured on an alignment plate (Oji CellArray-Heart) and on a commonly used flat plate. The alignment plate can make the seeded cardiomyocytes in automatic pulsating motion in a specific direction. Imaging of automated motor activities, mitochondria, and sarcomere were evaluated using instruments such as SI8000, FDSS and CQ1. We compared drug responses between two kinds of cardiomyocytes. Maturation factors were examined by RNA sequence and electrophysical response examined by patch clamp techniques.

[Results] The aligned iPSC-derived cardiomyocytes demonstrated increase in maturation, mitochondrial cell number, sarcomere alignment, heart rate and relaxation speed. RNA expression in various maturation key factors were also increased. Evidence of mature responses such as increased maximal diastolic potential, and prolonged action potential duration was observed. Several differences in drug responses such as the occurrence of arrhythmia were also observed between aligned and flat plate cardiomyocytes.

[Conclusion] We found that aligned iPS cell-derived cardiomyocytes promote maturation. These cells could be used as a tool for drug evaluation for adult myocardium, and would serve as hopeful candidate cells in cardiac regenerative medicine.