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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL117991-03
Application #
8828289
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wong, Renee P
Project Start
2013-07-15
Project End
2015-08-31
Budget Start
2015-05-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Hansen, Katrina J; Laflamme, Michael A; Gaudette, Glenn R (2018) Development of a Contractile Cardiac Fiber From Pluripotent Stem Cell Derived Cardiomyocytes. Front Cardiovasc Med 5:52
Smith, Alec S T; Macadangdang, Jesse; Leung, Winnie et al. (2017) Human iPSC-derived cardiomyocytes and tissue engineering strategies for disease modeling and drug screening. Biotechnol Adv 35:77-94
Hansen, Katrina J; Favreau, John T; Gershlak, Joshua R et al. (2017) Optical Method to Quantify Mechanical Contraction and Calcium Transients of Human Pluripotent Stem Cell-Derived Cardiomyocytes. Tissue Eng Part C Methods 23:445-454
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
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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
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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

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