Abstract 14493: Long-Term Survival Enables a High Quality of Electrical Integration of Transplanted Induced Pluripotent Stem Cell Derived Cardiomyocytes
Induced pluripotent stem cell-derived cardiomyocytes (iPSCM) are regarded as promising cell type for cardiac cell replacement therapy, but long-term survival and functional integration of transplanted iPSCM have not been demonstrated, yet. Thus, we investigated these fundamental mechanisms of an efficient and safe cell replacement therapy.
Methods: Murine iPSCM expressing eGFP and a puromycin resistance under control of the α-MHC promoter were purified by antibiotic selection. Purified iPSCM were injected into syngeneic adult hearts (2x 500,000 cells). 6-12 days, 3-6 weeks and 6-8 months after transplantation, recipients were sacrificed, and viable ventricular tissue slices (thickness: 150 μm) were prepared. Slices were focally stimulated by a unipolar electrode placed in host tissue. Action potential (AP) recordings were performed with glass microelectrodes in transplanted iPSCM and host cardiomyocytes within the tissue slices.
Results: Long-term persistence and electrical integration of transplanted iPSCM into recipient hearts could be clearly demonstrated. Coupling of transplanted iPSCM and host tissue was already observed 6-12 days after transplantation. At later time-points, transplanted iPSCM were still located in recipient hearts and showed improved electrical coupling to host tissue, as indicated by an average maximal stimulation frequency without conduction blocks of 5.99±0.51 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. The proportion of transplanted iPSCM, which were able to follow a stimulation frequency of 10 Hz without conduction blocks, increased from 0% at 6-12 days to ~10% at 3-6 weeks and ~60% at 6-8 months after transplantation. At all time-points, AP properties of transplanted iPSCM differed significantly from those of host cardiomyocytes.
Conclusions: Transplanted iPSCM 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. However, even after 6-8 months, AP properties of transplanted iPSCM differ from those of recipient cardiomyocytes, which may bear a proarrhythmic risk.
- © 2013 by American Heart Association, Inc.