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 #
5P01HL094374-03
Application #
8380419
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$664,941
Indirect Cost
$264,374
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Liu, Yen-Wen; Chen, Billy; Yang, Xiulan et al. (2018) Human embryonic stem cell-derived cardiomyocytes restore function in infarcted hearts of non-human primates. Nat Biotechnol 36:597-605
Hofsteen, Peter; Robitaille, Aaron Mark; Strash, Nicholas et al. (2018) ALPK2 Promotes Cardiogenesis in Zebrafish and Human Pluripotent Stem Cells. iScience 2:88-100
Neidig, Lauren E; Weinberger, Florian; Palpant, Nathan J et al. (2018) Evidence for Minimal Cardiogenic Potential of Stem Cell Antigen 1-Positive Cells in the Adult Mouse Heart. Circulation 138:2960-2962
Leonard, Andrea; Bertero, Alessandro; Powers, Joseph D et al. (2018) Afterload promotes maturation of human induced pluripotent stem cell derived cardiomyocytes in engineered heart tissues. J Mol Cell Cardiol 118:147-158
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
Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686
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

Showing the most recent 10 out of 93 publications