Project 1: Vascularization and Growth of Human Myocardial Grafts The goal of this project is to use lessons from cardiovascular development and stem ceU biology to create functional myocardium. Pluripotent human stem cells can now be directed to myocardial fates, yielding human myocardial cells that survive in the infarct, improve cardiac function and should be immunologically compatible with the host. Our central hypothesis is that significant growth and function of these grafts requires co-development of a coronary vascular supply, and that augmented vascularization will promote remuscularization.
Three specific aims are proposed.
Aim 1 builds on observations from tissue engineering, demonstrating that mouse fibroblasts and HUVECs cooperate with human cardiomyocytes in the formation of vascularized myocardial tissue. We will identify clinically relevant sources of mesenchymal cells and endothelium by screening MSC clones and endothelium derived from hESCs and EPCs, first in a cardiac tissue engineering and then in infarcted hearts.
Aim 2 explores the suitability of a novel cardiovascular progenitor cell derived from hESCs for cardiac repair. This multipotent mesodermal progenitor is identified by expression of KDR (VEGFR2) and is capable of generating human cardiomyocytes, endothelium and smooth muscle cells. We will test the ability of KDR-i- cells to form human myocardium and a human coronary circulation, which we predict will enhance myocardial graft size, myocardial blood flow and contractile function in the infarcted heart when compared to cardiomyocytes-only.
Aim 3 will investigate the mechanism through which cardiac grafts induce formation of collateral arteries from host coronaries, exploring the role of hedgehog signaling and the monocyte in promoting arterialization. These experiments address key questions regarding mechanisms of cardiac repair and are the first to systematically address formation of a human coronary circulation in combination with new myocardium.

Public Health Relevance

Stem cells offer the promise of remuscularizing the heart after injury. To date, however, stem cell-derived grafts are only a small fraction of the tissue originally lost. We propose that cardiac regeneration also requires growth of a new vascular supply. This project investigates the mechanisms through which muscle grafts become vascularized in the heart and uses stem cell and molecular approaches to enhance rpvaRriilariyatinn anri rpmiisriilariyatinn

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL094374-04
Application #
8485641
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$644,705
Indirect Cost
$257,140
Name
University of Washington
Department
Type
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

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