Pluripotent stem cells have demonstrated an ability to engraft in areas of myocardial damage, differentiate into cardiomyocytes, form intercalated disks and improve myocardial function. In a manuscript recently published, Dr. Dudley's laboratory has shown that stem cell derived cardiomyocytes have abnormal electrophysiology when developed in vitro, implying that these cells could contribute to arrhythmias. The overall hypothesis is that the failure of electrophysiological differentiation of pluripotent cells used for cell transplantation will be similar in an in vivo infarct model as it is in vitro. The alterations in current will be delineated as a starting point for possible transgenic amelioration strategies to render these cells less potentially arrhythmogenic.
Specific Aims : 1. To evaluate the cellular electrophysiology of pluripotent stem cells differentiated in an in vivo infarct model, delineating differences between native and stem cell derived cardiomyocytes in action potential morphology and proclivity for triggered arrhythmias. 2. To evaluate ion channel current differences that underlying changes in the changes seen in aim 1, using predominately voltage clamp techniques and further evaluation at the level of message and protein localization. Overall, this study will help to understand the electrophysiologic differentiation of stem cells in vivo and assess the basis of arrhythmogenicity associated with stem cell therapy for heart failure. ? ? ?
