Abstract 16862: Transfer of Exosome-Enclosed MicroRNAs From Host Myocardial Cells to Transplanted Cardiac Stem Cells Facilitates Improved Survival in the Ischemic Myocardium
Background: Despite the promises held by cardiac stem cells (CSCs) for restoration of cardiac function following MI, the poor survival of CSCs have been a major issue. Hypoxia-inducible factor 1-alpha (HIF-1α) is a transcription factor that mediates adaptive resonses to ischemia. Here we hypothesize that co-delivery of CSCs with minicircles-driven HIF-1α (MC-HIF1α) into the ischemic myocardium improves the survival of CSCs through exosomes.
Methods and Results: We subjected NOD/SCID mice (N=18/group) to LAD ligation followed by injection of either PBS, CSCs, CSCs+MC-HIF1α, or MC-HIFα into the peri-infarct region. One week after injection, we observed increased HIF-1α in endothelial cells (ECs) isolated from hearts where MC-HIFα was co-injected with CSCs (N=4, P<0.05). Bioluminescent imaging demonstrated improved survival of CSCs when co-injected with MC-HIF1α over a period of 21 days (N=6/group, P<0.05). Importantly, mice injected with CSCs+MC-HIF1a showed the highest ejection fraction at day 42 followed by MC-HIF1α alone (P<0.05) with no significant protection for CSCs alone compared to PBS as assessed by echo (N=8-10/group). To investigate potential mechanisms involved, we transfected an immortalized cardiac EC line with either MC-GFP (ECGFP) or MC-HIF1α (ECHIF1α). Exosomes purified from ECHIF1α conditioned medium had a higher content of the endothelial-specific miR-126 versus ECGFP (N=3, P<0.05). Importantly, CSCs grown in conditioned medium from ECHIF1α actively absorbed these exosomes. The transferred miR-126 was functionally active as determined by luciferase reporter assay, and along with activation of p-AKT led to increased resistance against simulated ischemic injury. This effect was abrogated when CSCs were grown in exosome-depleted conditioned medium demonstrating a direct effect of exosomes on increased ischemic tolerance (N=5/group, P<0.05).
Conclusions: In summary, these in vitro and in vivo studies demonstrated that HIF-1α can be used to modulate the microenvironment for improving survival of transplanted cells. Exosomal transfer of miRs from host cells to transplanted cells represents a previously undescribed and unique mechanism that can be potentially targeted for improving survival of transplanted cells.
- © 2013 by American Heart Association, Inc.