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

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Washington
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Hofsteen, Peter; Robitaille, Aaron M; Chapman, Daniel Patrick et al. (2016) Quantitative proteomics identify DAB2 as a cardiac developmental regulator that inhibits WNT/β-catenin signaling. Proc Natl Acad Sci U S A 113:1002-7
Ruan, Jia-Ling; Tulloch, Nathaniel L; Razumova, Maria V et al. (2016) Mechanical Stress Conditioning and Electrical Stimulation Promote Contractility and Force Maturation of Induced Pluripotent Stem Cell-Derived Human Cardiac Tissue. Circulation 134:1557-1567
Qin, Wan; Roberts, Meredith A; Qi, Xiaoli et al. (2016) Depth-resolved 3D visualization of coronary microvasculature with optical microangiography. Phys Med Biol 61:7536-7550
Pioner, Josè Manuel; Racca, Alice W; Klaiman, Jordan M et al. (2016) Isolation and Mechanical Measurements of Myofibrils from Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Stem Cell Reports 6:885-96
Kolwicz Jr, Stephen C; Odom, Guy L; Nowakowski, Sarah G et al. (2016) AAV6-mediated Cardiac-specific Overexpression of Ribonucleotide Reductase Enhances Myocardial Contractility. Mol Ther 24:240-50
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
Carson, Daniel; Hnilova, Marketa; Yang, Xiulan et al. (2016) Nanotopography-Induced Structural Anisotropy and Sarcomere Development in Human Cardiomyocytes Derived from Induced Pluripotent Stem Cells. ACS Appl Mater Interfaces 8:21923-32
Thies, R Scott; Murry, Charles E (2015) The advancement of human pluripotent stem cell-derived therapies into the clinic. Development 142:3077-84
Palpant, Nathan J; Hofsteen, Peter; Pabon, Lil et al. (2015) Cardiac development in zebrafish and human embryonic stem cells is inhibited by exposure to tobacco cigarettes and e-cigarettes. PLoS One 10:e0126259
Ruan, Jia-Ling; Tulloch, Nathaniel L; Saiget, Mark et al. (2015) Mechanical Stress Promotes Maturation of Human Myocardium From Pluripotent Stem Cell-Derived Progenitors. Stem Cells 33:2148-57

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