Electrophysiological integration and action potential properties of transplanted cardiomyocytes derived from induced pluripotent stem cells

摘要

Aims: Induced pluripotent stem cell-derived cardiomyocytes (i PSCM) are regarded as promising cell type for cardiac cell replacement therapy. We investigated long-term electrophysiological integration and maturation of transplanted i PSCM, which are essential for therapeutic benefit. Methods and results: Murine i PSCM expressing enhanced green fluorescent protein and a puromycin resistance under control of the α-myosin heavy chain promoter were purified by antibiotic selection and injected into adult mouse hearts. After 6-12 days, 3-6 weeks, or 6-8 months, viable slices of recipient hearts were prepared. Slices were focally stimulated by a unipolar electrode placed in host tissue, and intracellular action potentials (APs) were recorded with glass microelectrodes in transplanted cells and neighbouring host tissue within the slices. Persistence and electrical integration of transplanted i PSCM into recipient hearts could be demonstrated at all time points. Quality of coupling improved, as indicated by a maximal stimulation frequency without conduction blocks of 5.77+0.54 Hz at 6-12 days, 8.98+0.38 Hz at 3-6 weeks and 10.82+1.07 Hz at 6-8 months after transplantation. AP properties of i PSCM became more mature from 6-12 days to 6-8 months after transplantation, but still differed significantly from those of host APs. Conclusion: Transplanted i PSCM can persist in the long term and integrate electrically into host tissue, supporting their potential for cell replacement therapy. Quality of electrical integration improves between 6-12 days and 6-8 months after transplantation, and there are signs of an electrophysiological maturation. However, even after 6-8 months, AP properties oftrans-planted i PSCM differ from those of recipient cardiomyocytes.