Abstract 359: Human CD34+ Cell-Derived Exosomes Target Endothelial Cells to Deliver MiR-126 Promoting Revascularization and Myocardial Repair
Introduction: Locally transplanted human CD34+ stem cells have been shown to improve exercise tolerance in patients with myocardial ischemia and promote angiogenesis in animal models. Recently we have demonstrated that CD34+ cells secrete exosomes, membrane bound nano-vesicles, as a major component of their paracrine secretion which induces angiogenesis. We hypothesize that cell-free exosomes from CD34+ cells (CD34 Exo) mimic the beneficial effects of cells, and promote myocardial revascularization and repair via transfer of pro-angiogenic microRNAs, possibly to endothelial cells.
Methods and Results: Therapeutic potential of CD34 Exo isolated from equal number of adult human peripheral blood-derived CD34+ cells was evaluated in a murine model of myocardial ischemia (MI). Similar to cells, treatment with CD34 Exo resulted in significant improvement in ischemia compared to treatment with PBS (ejection fraction, 42±4 v 22±6%; capillary density, 113±7 v 66±6/HPF; fibrosis 27±2 v 48±7%, p<0.05, n=7-12). Interestingly, confocal imaging and flow cytometry analyses revealed that CD34 Exo was selectively internalized by endothelial cells when injected in to ischemic tissue. MicroRNA expression profiling and confirmatory tests indicated that CD34 Exo is significantly enriched with pro-angiogenic miRNAs such as miR126. Treatment of CD34 Exo increased miR126 expression specifically in endothelial cells of ischemic tissue; treatment of CD34 Exo lacking miR126 abolished that increase and diminished its pro-angiogenic function. This, and studies using fluorescent miR126 confirm that miR126 was directly transferred from CD34 Exo to endothelial cells, and that indirect increase of miR126 by other components of CD34 Exo was minimal. This data also suggests that miR126 is important for CD34 Exo function. Ongoing studies will test the role of transferred miR126 on modulation of proangiogenic gene expression pathways in endothelial cells lacking miR126 either by dicer, or, Egfl-7 knockdown.
Conclusion: CD34+ exosomes transfer miR126 to endothelial cells to induce angiogenesis and myocardial repair. The functional benefits associated with CD34+ cell therapy may be mediated by exosomes-mediated transfer of angiogenic microRNAs to endothelial cells.
- © 2013 by American Heart Association, Inc.