Physiological differences between transplanted and host tissue cause functional decoupling after in vitro transplantation of human embryonic stem cell-derived cardiomyocytes.
Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) might provide cells to repopulate injured myocardium. Electrical coupling of these cells to the host myocardium is a prerequisite for improved functionality. The aim of this study was to investigate electrical interaction of hESC-CMs with myocardial tissue and to identify factors challenging functional integration. Beating clusters containing hESC-CMs were cocultured in vitro with viable slices of late-stage embryonic murine ventricles. Field potentials recorded with micro-electrode arrays and video data were analyzed. The effects of heptanol, electrical pacing, beta-adrenergic, and muscarinic stimulation on coupling were studied. Beating clusters integrated morphologically and functionally resulting in a synchronized beating pattern after two to four days of coculture. Heptanol-induced conduction block between transplanted cells and host tissue and immunoreactivity for connexin43 suggested electrical coupling via gap junctions. Beta-adrenergic or muscarinic stimulation induced uncoupling and arrhythmias probably due to genetically determined differences of hormonal modulation of spontaneous beating rates of transplanted cells and host tissue. HESC-CMs can integrate functionally and develop synchronized beating. Interventions unraveling the different electrophysiological properties of transplanted and host tissue induce functional disintegration. Successful cellular replacement has to improve coupling but should also aim to transplant cardiomyocytes with similar electrophysiological properties as the host tissue.
Pillekamp
Frank
F
Pediatric Cardiology, University of Cologne, Cologne, Germany.
Halbach
Marcel
M
Reppel
Michael
M
Pfannkuche
Kurt
K
Nazzal
Rewa
R
Nguemo
Filomain
F
Matzkies
Matthias
M
Rubenchyk
Olga
O
Hannes
Tobias
T
Khalil
Markus
M
Bloch
Wilhelm
W
Sreeram
Narayanswami
N
Brockmeier
Konrad
K
Hescheler
Juergen
J
D000200:Action Potentials / Q000187:drug effects; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004594:Electrophysiology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000648:ultrastructure; D017629:Gap Junctions / Q000378:metabolism; D006329:Heart Conduction System / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D046529:Microscopy, Electron, Transmission; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects / Q000637:transplantation* / Q000648:ultrastructure
D000318:Adrenergic beta-Agonists