There is accumulating enthusiasm and experimental support for repairing damaged cardiac tissue using cell- based therapies. One of the most promising cell sources, supported by substantial pre-clinical data, is bone marrow derived mesenchymal stem cells (MSCs). We have shown that MSCs ameliorate the damage induced by anterior wall myocardial infarction (Ml) in a pig model of left anterior descending coronary artery occlusion. Of great clinical relevance, MSCs may be administered as an allogeneic graft and have received FDA approval to be studied for acute Ml. Several critical mechanistic issues require study in order to rationally advance the clinical development of MSCs as a therapy for acute and chronic cardiac injury. This program of work will examine a series of hypotheses regarding the mechanism of action of MSCs as an agent of cardiac repair.
In aim 1, we will test the hypothesis that MSCs stimulate cardiac repair by several mechanisms, including stimulation of endogenous repair mechanisms. We will utilize a well-established porcine model of Ml and administer GFP labeled MSCs. Cardiac repair will be monitored with cardiac MRI and multi-detector CT and cardiac tissue will be submitted to confocal microscopy to quantify cell engraftment, differentiation, and the proliferation of endogenous cell sources.
Aim 2 will address several critical issues regarding MSC therapy. We will compare autologous and allogeneic MSCs both at functional and molecular/cellular levels to address whether allogeneic cells are equivalent to autologous cells as an agent of cardiac repair. Additionally, we will test the hypothesis that MSCs are superior to whole bone marrow mononuclear preparations, and finally we will assess various cell delivery methods.
In aim 3, we will perform studies in 2 established heart failure (HF) models - chronic ischemic cardiomyopathy and pacing induced HF. MSC efficacy in chronic HF will be assessed using comprehensive evaluation of myocardial performance including cardiac magnetic resonance imaging (MRI), hemodynamic pressure-volume catheterization, and electrophysiology testing. The results of this aim have the potential to broaden the patient population eligible to receive cellular myoplasty. Together, these experiments will advance the translational and mechanistic understanding of cellular myoplasty using MSCs and evaluate whether these cells represent a novel treatment for a wide range of acute and chronic structural heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084275-05
Application #
8082682
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Buxton, Denis B
Project Start
2007-07-05
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$382,500
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
Tompkins, Bryon A; Natsumeda, Makoto; Balkan, Wayne et al. (2017) What Is the Future of Cell-Based Therapy for Acute Myocardial Infarction. Circ Res 120:252-255
Kanelidis, Anthony J; Premer, Courtney; Lopez, Juan et al. (2017) Route of Delivery Modulates the Efficacy of Mesenchymal Stem Cell Therapy for Myocardial Infarction: A Meta-Analysis of Preclinical Studies and Clinical Trials. Circ Res 120:1139-1150
Gesmundo, Iacopo; Miragoli, Michele; Carullo, Pierluigi et al. (2017) Growth hormone-releasing hormone attenuates cardiac hypertrophy and improves heart function in pressure overload-induced heart failure. Proc Natl Acad Sci U S A 114:12033-12038
Natsumeda, Makoto; Florea, Victoria; Rieger, Angela C et al. (2017) A Combination of Allogeneic Stem Cells Promotes Cardiac Regeneration. J Am Coll Cardiol 70:2504-2515
Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686
Golpanian, Samuel; Schulman, Ivonne H; Ebert, Ray F et al. (2016) Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease. Stem Cells Transl Med 5:186-91
Bellio, Michael A; Balkan, Wayne; Hare, Joshua M et al. (2016) Is the regulation of SIRT1 by miRNA-34a the key to mesenchymal stem cell survival? Ann Transl Med 4:243
White, Ian A; Sanina, Cristina; Balkan, Wayne et al. (2016) Mesenchymal Stem Cells in Cardiology. Methods Mol Biol 1416:55-87
Hatzistergos, Konstantinos E; Hare, Joshua M (2016) Murine Models Demonstrate Distinct Vasculogenic and Cardiomyogenic cKit+ Lineages in the Heart. Circ Res 118:382-7
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

Showing the most recent 10 out of 88 publications