Stem Cells and Cardiovascular Repair: We propose a comprehensive program on myocardial infarct repair using adult and pluripotent human stem cells, with an emphasis on pre-clinical translation. There are 3 projects and 3 cores. Project 1 (Murry, Schwartz, Mahoney) focuses on vascularization, beginning with transplants of clinically relevant sources of human cardiomyocytes, endothelium and MSCs. Next, they transplant a multipotent human cardiovascular progenitor from ESCs, capable of generating cardiomyocytes, endothelium and smooth muscle, to generate vascularized myocardium in the infarct. Finally, they explore mechanisms through which grafts induce collateral arterialization from the host coronaries. Project 2 (Laflamme, Santana) studies the electro-physiology of human cardiomyocytes, using genetic selection to generate pacemaker vs. working-type cells. They will identify signaling pathways that specify hESC-derived myocytes into working-type vs. pacemaker phenotypes, with a goal of determining if pacemaker cells are precursors of the working-type cells or a separate stable branch. Lastly, they use cell transplantation to assess the ability of the different myocyte subtypes to couple with host cardiomyocytes and test their differential effects on electrical stability. Project 3 (Torok-Storb, Bowen-Pope) develops a pre-clinical model in the dog for cardiac repair. They will generate a system for scalable production of cardiomyocytes from their recently generated canine induced pluripotent stem cells (iPSCs). Next, they investigate if MSCs can pro-mote repair by endogenous cells and exogenous cardio-myocytes, including testing if MSCs induce third-party tolerance to allogeneic cardiomyocytes. Finally, they perform transplantation studies with canine iPSC-derived cardiomyocytes and MSCs, creating a clinically relevant model of cardiac stem cell therapy in the dog. Projects are supported by a Stem Cell Core (A) that trains investigators in hESC use and provides differentiated cells i.e., cardiomyocytes;an Out-comes Core (B) provides histology services, a central source of expertise in animal models of myocardial infarction, cell transplantation and physiological assessment;and an Administrative Core (C) to coordinate meetings, seminar series, provide fiscal support and plan the annual PPG retreat.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL094374-03
Application #
8327805
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Lundberg, Martha
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$2,529,403
Indirect Cost
$904,201
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
Jiao, Alex; Trosper, Nicole E; Yang, Hee Seok et al. (2014) Thermoresponsive nanofabricated substratum for the engineering of three-dimensional tissues with layer-by-layer architectural control. ACS Nano 8:4430-9
Chong, James J H; Murry, Charles E (2014) Cardiac regeneration using pluripotent stem cells--progression to large animal models. Stem Cell Res 13:654-65
Coulombe, Kareen L K; Bajpai, Vivek K; Andreadis, Stelios T et al. (2014) Heart regeneration with engineered myocardial tissue. Annu Rev Biomed Eng 16:1-28
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
Hartman, Matthew E; Liu, Yonggang; Zhu, Wei-Zhong et al. (2014) Myocardial deletion of transcription factor CHF1/Hey2 results in altered myocyte action potential and mild conduction system expansion but does not alter conduction system function or promote spontaneous arrhythmias. FASEB J 28:3007-15
Yang, Xiulan; Pabon, Lil; Murry, Charles E (2014) Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Res 114:511-23
Thomson, Kassandra S; Dupras, Sarah K; Murry, Charles E et al. (2014) Proangiogenic microtemplated fibrin scaffolds containing aprotinin promote improved wound healing responses. Angiogenesis 17:195-205
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
Bahrami, Arya J; Gunaje, Jagadambika J; Hayes, Brian J et al. (2014) Regulator of G-protein signaling-5 is a marker of hepatic stellate cells and expression mediates response to liver injury. PLoS One 9:e108505

Showing the most recent 10 out of 44 publications