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. Our published studies demonstrate that rat cardiac progenitor cells (CPCs) make exosomes, and when cells are exposed to hypoxia, exosomes are reparative following infarction. Moreover, we were able to demonstrate potential pathways using computational and systems biology. Recently, we have been able to isolate CPCs from pediatric biopsies and show age-related changes in cell therapy in a model of heart failure. Preliminary studies demonstrate that these exosomes also vary in function by age and hypoxia. Therefore, the objective of this proposal is to examine the protective/regenerative capacity of human pediatric CPC exosomes in rat models of ischemia-reperfusion. Additionally, with a large number of patient samples from a wide variety of children, 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. Finally, we will expand our model by looking at reparative exosomes from other cell types, CD34+ cells, and examine whether mechanisms of hypoxic exosome function are conserved among different cells. 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.
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.
