Because of their tremendous capacity for in vitro expansion and ability to differentiate into phenotypically unambiguous cardiomyocytes, pluripotent human embryonic stem cells (hESCs) are an attractive source for cell-based cardiac therapies. Our group has exciting new data indicating that hESC-derived cardiomyocytes (hESC-CMs) can couple with host myocardium following transplantation in guinea pig hearts, but their integration is imperfect in injured hearts. We have also found that hESC-CM transplantation significantly decreases the incidence of both spontaneous and induced arrhythmias. The present application builds on these observations and has two overall goals: first, to determine the mechanistic basis for this arrhythmia-suppressive effect and, second, to test novel approaches to further enhance the electromechanical integration of hESC-CMs in injured hearts.
In Aim 1, we will test the hypothesis that the beneficial effects of hESC-CM transplantation on electrical stability correlates with their functional incorporation.
In Aim 2, w will test the hypothesis that treatment with gap-junction modifiers will improve host-graft coupling following hESC-CM transplantation in a guinea pig infarct model. Finally, in Aim 3, we will use in vitro models to develop Wnt5a-mediated chemotaxis as a complementary strategy to improve the integration of hESC-CM grafts.
Arrhythmias are a major cause of death after a myocardial infarction (heart attack), but preliminary studies suggest that the transplantation of stem-cell-derived cardiomyocytes (heart muscle cells) can greatly reduce the incidence of post-infarct arrhythmias. The experiments proposed in this application will investigate the mechanistic basis for this anti-arrhythmic effect and explore new strategies to further enhance the electrical integration of stem-cell-derived cardiomyocytes in injured hearts.
|Hartman, Matthew E; Dai, Dao-Fu; Laflamme, Michael A (2016) Human pluripotent stem cells: Prospects and challenges as a source of cardiomyocytes for in vitro modeling and cell-based cardiac repair. Adv Drug Deliv Rev 96:3-17|
|Posnack, Nikki Gillum; Idrees, Rabia; Ding, Hao et al. (2015) Exposure to phthalates affects calcium handling and intercellular connectivity of human stem cell-derived cardiomyocytes. PLoS One 10:e0121927|
|Kuppusamy, Kavitha T; Jones, Daniel C; Sperber, Henrik et al. (2015) Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes. Proc Natl Acad Sci U S A 112:E2785-94|
|Lundy, Scott D; Gantz, Jay A; Pagan, Chelsea M et al. (2014) Pluripotent stem cell derived cardiomyocytes for cardiac repair. Curr Treat Options Cardiovasc Med 16:319|
|Murry, Charles E; Chong, James J H; Laflamme, Michael A (2014) Letter by Murry et al regarding article, "Embryonic stem cell-derived cardiac myocytes are not ready for human trials". Circ Res 115:e28-9|
|Chong, James J H; Yang, Xiulan; Don, Creighton W et al. (2014) Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510:273-7|
|Zhu, Wei-Zhong; Filice, Dominic; Palpant, Nathan J et al. (2014) Methods for assessing the electromechanical integration of human pluripotent stem cell-derived cardiomyocyte grafts. Methods Mol Biol 1181:229-47|
|Shiba, Yuji; Filice, Dominic; Fernandes, Sarah et al. (2014) Electrical Integration of Human Embryonic Stem Cell-Derived Cardiomyocytes in a Guinea Pig Chronic Infarct Model. J Cardiovasc Pharmacol Ther 19:368-381|
|Lundy, Scott D; Murphy, Sean A; Dupras, Sarah K et al. (2014) Cell-based delivery of dATP via gap junctions enhances cardiac contractility. J Mol Cell Cardiol 72:350-9|
|Nunes, Sara S; Miklas, Jason W; Liu, Jie et al. (2013) Biowire: a platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Nat Methods 10:781-7|