Abstract 20041: Human CD34+ Stem Cell-Derived Exosomes Mediate the Paracrine miRNA-Crosstalk with Cardiomyocytes and Endothelial Cells Promoting Repair of the Ischemic Heart
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. Earlier in a study, first of its kind, we have demonstrated a novel mechanism that CD34+ cells secrete membrane bound nano-vesicles called exosomes (CD34Exo) into their paracrine secretion. CD34Exo are angiogenic and constitute a critical component of the pro-angiogenic paracrine activity of the cells.
Hypothesis: Cell-free CD34Exo may mimic the beneficial effects of the cells, and promote angiogenesis and ischemic tissue repair via transferring pro-angiogenic microRNAs.
Methods and Results: We used a murine model of myocardial ischemia to determine the therapeutic efficacy of CD34Exo. Cell-free CD34Exo replicated the therapeutic activity of their parent cells by significantly improving myocardial ischemia (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) compared with a PBS control. Trafficking studies using confocal imaging and flow cytometry analyses revealed that CD34Exo was selectively internalized mostly into endothelial cells and cardiomyocytes but not into fibroblasts in the CD34Exo-injected ischemic hearts. MicroRNA expression profiling and Taqman assays indicated that CD34Exo are significantly enriched with pro-angiogenic miRNAs such as miR126. CD34Exo injection induced the expression of miR126 and several pro-angiogenic mRNAs in mouse ischemic myocardium, but did not affect the endogenous synthesis of miR126, suggesting a direct transfer of miR126. CD34Exo lacking in miR126 had decreased angiogenic and therapeutic activity both in vitro and in vivo indicating that miR126 was important for CD34Exo function.
Conclusions: Our results reveal a novel molecular and trafficking mechanism of CD34Exo in vivo that are selectively uptaken by endothelial cells and cardiomyocytes, transferring stem cell-specific miRNAs and possibly other contents, inducing changes in gene expression, angiogenesis and myocardial recovery. Exosomes-shuttled miRNAs may signify amplification of stem cell function and may explain the therapeutic benefits associated with human CD34+ cell therapy.
Author Disclosures: D. Kim: None. D.E. Vaughan: None. S.E. Quaggin: None. D.W. Losordo: None. S. Sahoo: Research Grant; Significant; AHA-SDG.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.