Adverse remodeling of the myocardium after myocardial infarction speeds progression to heart failure. While cell therapy has been met with great enthusiasm, there are numerous shortcomings that prevent long-term functional improvements. Moreover, these cells come from diseased individuals and immunogenicity limits most studies to autologous therapy. Finally, it is widely believed that the main effect of cell therapy is mediated by paracrine effectors and not the cells themselves. We have isolated rat and human cardiac progenitor cells that are cardiac-derived, express c-kit, do not express any markers of cardiogenic lineage, but can differentiate in to all cardiac cell types. These cells basally release microRNA (miR) in to the extracellular space. When treated with hypoxic conditions, these cells increase cardioprotective miRs within exosomes. Preliminary studies demonstrate that these hypoxic exosomes enhance endothelial cell tube formation and decrease fibrotic gene expression in fibroblasts. Therefore, the objective of this proposal is to examine the protective/regenerative capacity of these exosomes in rat models of ischemia-reperfusion. Additionally, with a large number of patient samples from children and adults, we can perform multivariate analysis to examine the factors that affect various in vivo mechanisms. Factors include patient age, gender, and exposure to hypoxic conditions. Completion of the proposed studies will determine whether hypoxic exosomes are a beneficial therapy for ischemia-reperfusion injury, as well as determine potential patient factors that contribute to these responses.

Public Health Relevance

Cardiovascular disease is a leading cause of morbidity and mortality worldwide and effective treatment options are greatly needed. Cell therapy trials show promise, but many hurdles still remain. We propose that delivery of exosomes containing microRNAs from human cardiac progenitor cells will improve cardiac function, as well as allow us to elucidate potential mechanisms through computational analysis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
High Priority, Short Term Project Award (R56)
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Gene and Drug Delivery Systems Study Section (GDD)
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Wong, Renee P
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Emory University
Biomedical Engineering
Schools of Medicine
United States
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Agarwal, Udit; George, Alex; Bhutani, Srishti et al. (2017) Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell-Derived Exosomes From Pediatric Patients. Circ Res 120:701-712
Agarwal, Udit; Smith, Amanda W; French, Kristin M et al. (2016) Age-Dependent Effect of Pediatric Cardiac Progenitor Cells After Juvenile Heart Failure. Stem Cells Transl Med 5:883-92
Davis, Michael E (2016) Exosomes: What Do We Love So Much About Them? Circ Res 119:1280-1282
Gray, Warren D; French, Kristin M; Ghosh-Choudhary, Shohini et al. (2015) Identification of therapeutic covariant microRNA clusters in hypoxia-treated cardiac progenitor cell exosomes using systems biology. Circ Res 116:255-63