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
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Hofsteen, Peter; Robitaille, Aaron Mark; Strash, Nicholas et al. (2018) ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells. iScience 2:88-100
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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
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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
Palpant, Nathan J; Wang, Yuliang; Hadland, Brandon et al. (2017) Chromatin and Transcriptional Analysis of Mesoderm Progenitor Cells Identifies HOPX as a Regulator of Primitive Hematopoiesis. Cell Rep 20:1597-1608
Palpant, Nathan J; Pabon, Lil; Friedman, Clayton E et al. (2017) Generating high-purity cardiac and endothelial derivatives from patterned mesoderm using human pluripotent stem cells. Nat Protoc 12:15-31
Yang, Xiulan; Murry, Charles E (2017) One Stride Forward: Maturation and Scalable Production of Engineered Human Myocardium. Circulation 135:1848-1850

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