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1 Indiana University
2 Indiana University School of Medicine
* To whom correspondence should be addressed. E-mail: dmeldrum{at}iupui.edu.
Bone marrow stem cells (MSCs) may be a novel treatment modality for organ ischemia, possibly through the release of beneficial paracrine factors. However, an age threshold likely exists as to when MSCs gain their beneficial protective properties. We hypothesized that 1) VEGF would be a crucial stem cell paracrine mediator in providing post-ischemic myocardial protection, and 2) siRNA ablation of VEGF in adult MSCs (aMSCs) would equalize the differences observed between adult and neonatal (nMSC) stem cell mediated cardioprotection. Female adult Sprague-Dawley rat hearts were subjected to ischemia/reperfusion injury via Langendorff isolated heart preparation (15 minutes equilibration, 25 minutes ischemia, 60 minutes reperfusion). MSCs were harvested from adult and 2.5 week old neonatal mice and cultured under normal conditions. VEGF was knocked down in both cell lines by VEGF siRNA. Immediately prior to ischemia, one million adult or neonatal MSCs with or without VEGF knockdown were infused into the coronary circulation. Cardiac functional parameters were recorded. VEGF in cell supernatants was measured via ELISA. aMSCs produced significantly more VEGF than nMSCs, and were noted to increase post-ischemic myocardial recovery compared to nMSCs. Knockdown of VEGF significantly decreased VEGF production in both cell lines, and pretreatment of these cells impaired stem cell mediated myocardial function. Knockdown of VEGF in adult stem cells equalized the myocardial functional differences observed between adult and neonatal stem cells. Therefore, VEGF is a critical paracrine mediator in facilitating post-ischemic myocardial recovery, and likely plays a role in mediating the observed age threshold during stem cell therapy.
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