Major progress has been made in the understanding and translational advancement of cell-based therapeutics for chronic ischemic heart disease, a condition affecting approximately 5 million Americans. We have used the first funding period of this award to develop sophisticated porcine models of ischemic cardiomyopathy characterized by progressive ventricular remodeling. Using this model we have tested several strategies for cell-based therapeutics, gleaned major mechanistic insights, and developed sufficient preclinical data to be able to initiate clinical trials. Importantly, we showed that engraftment and differentiation of mesenchymal stem cells (MSCs) in the injured porcine heart was accompanied by 1) gap junction formation with host cells, 2) stimulation of endogenous cardiac stem cell (CSC) proliferation and differentiation and 3) sustained reverse remodeling and contractile restoration in myocardial areas of prior chronic ischemic dysfunction. In preliminary findings, we also showed that combining MSCs with CSCs leads to substantially greater efficacy at infarct size reduction. In this renewal application, we propose to identify the molecular underpinnings of this novel cell- based therapeutic strategy for ischemic cardiomyopathy using our established porcine model. Accordingly, we propose a series of three aims designed to test novel mechanistic hypotheses regarding MSC and CSC-based cardiac regeneration. We propose to 1) establish the mechanisms underlying the improved infarct scar reduction resulting from a combination of autologous CSCs and MSCs, 2) assess the impact of cell-cell communication by connexin 43 (Cx43)-mediated gap junctions on cardiac regeneration, and 3) assess the cell- cell interaction and efficacy of pharmacologically and/or genetically modified CSCs for myocardial repair in ischemic cardiomyopathy. These studies will continue our trajectory of work designed to obtain the most robust preclinical data possible to enlarge our knowledge base of the mechanisms underlying cell-based therapy for chronic ischemic heart disease. The proposed studies are timely, warranted, and could have a major health impact by addressing an unmet need in a large population of patients at risk for progressive heart failure, lifelong disability, sudden cardiac death, and recurrent hospitalizations. The approaches employed are well validated by our group and include in vitro and in vivo experimental models and efficient cell delivery systems and state of the art imaging strategies currently in use by our group. Our mechanistic research program has high translational value and is highly significant, as cellular therapy offers the potential to regenerate new myocardium and decrease progression of heart failure in patients with left ventricular dysfunction due to healed myocardial infarction. Together, these aims will advance our understanding of the mechanisms underlying cell- based therapy for chronic ischemic heart disease, with specific emphasis placed upon the impact of a combination of cell types and modulation of molecular mechanisms that can have additive or synergistic properties, thereby enhancing the efficacy and durability of cell therapy for ischemic cardiomyopathy.
This preclinical study will address a significant clinical need, namely the investigation of mechanisms of action of new and promising cell-based therapies for heart dysfunction due to heart attack. This is one of the leading causes of cardiovascular death and disability. The proposed studies will elucidate new mechanistic insights for enhancing the clinical efficacy and safety of cell-based therapy for the treatment of this common and important disorder.
| 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 |
| Starke, Robert M; Thompson, John W; Ali, Muhammad S et al. (2018) Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis. Arterioscler Thromb Vasc Biol 38:610-621 |
| Bolli, Roberto; Hare, Joshua (2018) Introduction to a Compendium on Regenerative Cardiology. Circ Res 123:129-131 |
| 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 |
| Eschenhagen, Thomas; Bolli, Roberto; Braun, Thomas et al. (2017) Cardiomyocyte Regeneration: A Consensus Statement. Circulation 136:680-686 |
| Tompkins, Bryon A; Rieger, Angela C; Florea, Victoria et al. (2017) New insights into cell-based therapy for heart failure from the CHART-1 study. Eur J Heart Fail 19:1530-1533 |
| Fernández-Avilés, Francisco; Sanz-Ruiz, Ricardo; Climent, Andreu M et al. (2017) Global position paper on cardiovascular regenerative medicine. Eur Heart J 38:2532-2546 |
| 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 |
| 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 |
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