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.

Agency
National Institute of Health (NIH)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56HL124380-01
Application #
8903585
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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