Recently, pluri-potent cells have shown the ability to engraft in areas of myocardial damage, to differentiate into cardiomyocytes (CMs), to form intercalated disks, and to improve cardiac function. In a manuscript recently published in Circulation, the laboratory demonstrates these cells could contribute to arrhythmias. The overall hypotheses are that toti-potent stem cells used for cell transplantation therapy will be arrhythmogenic because of abnormal electrophysiological differentiation and that the choice of stem cells can overcome this limitation. The key questions that will be answered are: 1) Is electrophysiological differentiation abnormal in vivo? 2) Will electrophysiological differentiation be influenced by the injury milieu? 3) Do any of the cellular electrophysiological abnormalities result in arrhythmia? 4) Can arrhythmic risk be mitigated while retaining the benefits of cell transplantation by proper selection of precursor cells? Specific Objectives. 1. To assess the significance of totipotent stem cell transplant electrophysiology on mouse whole animal arrhythmic risk markers in the presence and absence of injury. 2. To evaluate the electrophysiology of totipotent stem cells differentiated in vivo in the presence or absence of injury, delineating differences between CMs and control myocytes and assessing the impact of differentiation environment on cellular electrophysiology. 3. To test 1 alternative strategy for improving myocardial function and reducing arrhythmic risk by transplanting bone marrow derived, hemangioblastic cells as therapy for myocardial injury. In addition to representing possibly strategies to retain the benefits of cell transplantation and simultaneously minimize any risk of arrhythmia, the experiments in aim 3 will test whether the improvement in myocardial function depends on the synchronized contraction of CMs.
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