Ischemic heart disease is a leading cause of death worldwide. Given the limited regenerative capacity of the human heart following myocardial injury, stem cell-based therapies, including the recent cKit+ cell therapy have emerged as a promising approach for improving cardiac repair and function. Clinical and preclinical data suggests that benefits of cKit+ cell transplantation include improved cardiac function and myocardial mass. However, the ability of cKit+ CPCs to differentiate into cardiomyocytes as a significant mode of cardiac repair is controversial. Published data from our group has established the beneficial effects of stem cell factor (SCF), the ligand for cKit, in improving the abundance of cKit+ cells, angiogenesis and cardiac function in both rat and pig models of ischemic cardiomyopathy. Further, our preliminary data suggest that secreted paracrine factors, particularly the membrane-bound exosomes, may mediate most of the pro-angiogenic paracrine activity of the SCF-treated cKit+ cell. Our central hypothesis is that mobilization of a heterogeneous group of endogenous CPCs using gene transfer for the receptor tyrosine cKit ligand stem cell factor (SCF) can enhance cardiac tissue repair following myocardial injury via their paracrine secretion. We will test the necessary and sufficient conditions of SCF-induced CPC recruitment using the MI model of heart failure in swine to evaluate the roles of SCF-induced cKit, PW1 and PDGFR? expressing CPCs in myocardial repair, regeneration and restoration of function. We will test the hypothesis that cKit, PW1 and PDGFR? progenitor cells are sufficient for SCF induced cardiac repair by gain of function experiments using SCF modRNA. We will test the hypothesis that cKit, PW1 and PDGFR? progenitor cells are necessary for cardiac repair by loss of function experiments using shRNA-mediated knockdown of cKit, PDGFR? and PW1 receptors. RNAs will be delivered one-week post-MI by the clinically relevant intracoronary route and animals will be evaluated for survival, cardiac remodeling, cardiac function, cell-specific proliferation and differentiation and the molecular mechanisms involved. We will determine the role of paracrine secretion from cKit+ CPCs in SCF-induced cardiac repair. Our preliminary data suggest that exosomes, and not the exosomes-depleted fraction from swine post-MI cKit- secretome have pro-angiogenic activity. Using specific expertise for exosomes research, we will identify the miRNA expression of cKit+ exosomes in response to SCF. In addition, we will investigate the functional mechanisms of cKit+ exosomes-induced proliferation and contractile function of cardiomyocytes and angiogenesis of endothelial cells in vitro. Finally, we will determine the therapeutic benefits of cKit exosomes in a swine model of heart failure.

Public Health Relevance

We propose to examine the roles cardiac progenitor cells (CPCs) in the heart failure as a foundation for understanding their endogenous regenerative potential. We have designed a program to investigate novel SCF encoding modified mRNA nanoparticle activation of endogenous CPCs and their paracrine effects. Our program focuses on using innovative delivery vector and state of the art genomics technologies to examine the CPC basic biology, reparative potential and impacts after myocardial function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL135093-01
Application #
9220049
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Buxton, Denis B
Project Start
2017-01-20
Project End
2020-12-31
Budget Start
2017-01-20
Budget End
2017-12-31
Support Year
1
Fiscal Year
2017
Total Cost
$840,689
Indirect Cost
$344,707
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Levine, Robert A; Jerosch-Herold, Michael; Hajjar, Roger J (2018) Mitral Valve Prolapse: A Disease of Valve and Ventricle. J Am Coll Cardiol 72:835-837
Mayourian, Joshua; Ceholski, Delaine K; Gorski, Przemek A et al. (2018) Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility. Circ Res 122:933-944
Ishikawa, Kiyotake; Watanabe, Shin; Lee, Philyoung et al. (2018) Acute Left Ventricular Unloading Reduces Atrial Stretch and Inhibits Atrial Arrhythmias. J Am Coll Cardiol 72:738-750
Ceholski, Delaine K; Turnbull, Irene C; Kong, Chi-Wing et al. (2018) Functional and transcriptomic insights into pathogenesis of R9C phospholamban mutation using human induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol 119:147-154
Oh, Jae Gyun; Watanabe, Shin; Lee, Ahyoung et al. (2018) miR-146a Suppresses SUMO1 Expression and Induces Cardiac Dysfunction in Maladaptive Hypertrophy. Circ Res 123:673-685
Chamberlain, Kyle; Riyad, Jalish M; Garnett, Tyrone et al. (2018) A Calsequestrin Cis-Regulatory Motif Coupled to a Cardiac Troponin T Promoter Improves Cardiac Adeno-Associated Virus Serotype 9 Transduction Specificity. Hum Gene Ther 29:927-937
Michelis, Katherine C; Nomura-Kitabayashi, Aya; Lecce, Laura et al. (2018) CD90 Identifies Adventitial Mesenchymal Progenitor Cells in Adult Human Medium- and Large-Sized Arteries. Stem Cell Reports 11:242-257
Watanabe, Shin; Ishikawa, Kiyotake; Plataki, Maria et al. (2018) Safety and long-term efficacy of AAV1.SERCA2a using nebulizer delivery in a pig model of pulmonary hypertension. Pulm Circ 8:2045894018799738
Jeong, Dongtak; Yoo, Jimeen; Lee, Philyoung et al. (2018) miR-25 Tough Decoy Enhances Cardiac Function in Heart Failure. Mol Ther 26:718-729
Stroik, Daniel R; Yuen, Samantha L; Janicek, Kevyn A et al. (2018) Targeting protein-protein interactions for therapeutic discovery via FRET-based high-throughput screening in living cells. Sci Rep 8:12560

Showing the most recent 10 out of 22 publications