Cell therapy for chronic ischemic cardiomyopathy is important and ready for investigation. The myocardium has very limited regenerative potential after infarction, but we and others have shown that regenerative mechanisms do exist, exhibit plasticity, and can be harnessed and amplified towards therapeutic goals. While significant attention has been paid to bone marrow derived cells, it is increasingly appreciated that the heart itself contains resident cardiac stem cells (CSCs) with the potential to differentiate into cardiomyocytes, vascular smooth muscle cells, and endothelial cells. We have found that therapeutic administration of MSCs is followed by dramatic stimulation of host CPCs in vivo, which are recruited to and/or amplified at the site of MSC injection, and which regenerate infarcted myocardium by differentiation into functional cardiomyocytes. These CSCs are a potential therapeutic agent. The overall aim of this project is the preclinical validation of c-kit+ CPC therapy for an FDA IND for a clinical trial. Our in vivo findings demonstrate that the activation of endogenous CPCs by transplanted MSCs results in the replacement of the damaged heart. Additional preliminary data shows that bone marrowderived MSCs, when used as a feeder layer in organotypic cultures of porcine endomyocardial biopsies, hasten a dramatic outgrowth of c-kit+ CPCs with enhanced cardioblastic properties. Here, we hypothesize that adult c-kit+ cardioblasts can be optimally generated from single endomyocardial biopsies, and can be successfully expanded into therapeutic quantities. We will transplant c-kit+ CPCs alone and in combination with MSCs into a validated preclinical model of heart failure, the Gottingen miniswine. The goals of this work are to obtain safety and efficacy data to support an FDA IND, and to study the regenerative effects of these cell-based therapeutic strategies. Accordingly, this study will support the transition of CPCs from the laboratory to clinical practice. This program of work will allow an orderly progression of studies with the overall aim of developing a novel cell-based therapy that will address major unmet needs in cardiovascular medicine.

Public Health Relevance

Cell-based therapies for myocardial infarction are currently under evaluation and are emerging as a promising new therapy. Here we propose the use of highly cardiopoetic cardiac progenitor cells. Cells will be tested in a porcine model in preparation for an FDA IND. The results of this trial will advance the field greatly by introducing a novel cell-based therapy for chronic ischemic heart disease,

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory Grants (P20)
Project #
5P20HL101443-02
Application #
8011520
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (F1))
Program Officer
Adhikari, Bishow B
Project Start
2010-04-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2011
Total Cost
$763,799
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Hatzistergos, Konstantinos E; Saur, Dieter; Seidler, Barbara et al. (2016) Stimulatory Effects of Mesenchymal Stem Cells on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways. Circ Res 119:921-30
Suncion, Viky Y; Ghersin, Eduard; Fishman, Joel E et al. (2014) Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial. Circ Res 114:1292-301
Karantalis, Vasileios; DiFede, Darcy L; Gerstenblith, Gary et al. (2014) Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The Prospective Randomized Study of Mesenchymal Stem Ce Circ Res 114:1302-10
Heldman, Alan W; DiFede, Darcy L; Fishman, Joel E et al. (2014) Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 311:62-73
Premer, Courtney; Hare, Joshua M (2014) Can endothelial progenitor cells treat patients with refractory angina? Circ Res 115:904-7
Williams, Adam R; Suncion, Viky Y; McCall, Frederic et al. (2013) Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling. J Am Heart Assoc 2:e000140
Williams, Adam R; Hatzistergos, Konstantinos E; Addicott, Benjamin et al. (2013) Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation 127:213-23
Da Silva, Jose S; Hare, Joshua M (2013) Cell-based therapies for myocardial repair: emerging role for bone marrow-derived mesenchymal stem cells (MSCs) in the treatment of the chronically injured heart. Methods Mol Biol 1037:145-63
Telukuntla, Kartik S; Suncion, Viky Y; Schulman, Ivonne H et al. (2013) The advancing field of cell-based therapy: insights and lessons from clinical trials. J Am Heart Assoc 2:e000338
Hare, Joshua M; Fishman, Joel E; Gerstenblith, Gary et al. (2012) Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 308:2369-79

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