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

Induced pluripotent stem cell-derived cardiomyocytes (iPSCM) are regarded as promising cell type for cardiac cell replacement therapy. We investigated long-term electrophysiological integration and maturation of transplanted iPSCM, which are essential for therapeutic benefit. Murine iPSCM expressing enhanced green fluorescent protein and a puromycin resistance under control of the -myosin heavy chain promoter were purified by antibiotic selection and injected into adult mouse hearts. After 612 days, 36 weeks, or 68 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 iPSCM 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 612 days, 8.98 0.38 Hz at 36 weeks and 10.82 1.07 Hz at 68 months after transplantation. AP properties of iPSCM became more mature from 612 days to 68 months after transplantation, but still differed significantly from those of host APs. Transplanted iPSCM 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 612 days and 68 months after transplantation, and there are signs of an electrophysiological maturation. However, even after 68 months, AP properties of transplanted iPSCM differ from those of recipient cardiomyocytes.