Pretreating mesenchymal stem cells with interleukin-1β and transforming growth factor-β synergistically increases vascular endothelial growth factor production and improves mesenchymal stem cell-mediated myocardial protection after acute ischemia

Background. Mesenchymal stem cells (MSCs) improve postischemic myocardial function in. part through their secretion of growth factors such as vascular endothelial growth factor (VEGF). Pretreating MSCs with various cytokines or small molecules can improve VEGF secretion and MSC-mediated cardioprotection. However, whether 1 cytokine can potentiate the effect of another cytokine in MSC pretreatment to achieve a synergistic effect on VEGF production and cardioprotection is poorly studied. Methods. MSCs were treated with interleukin (IL)-1 beta and/or transforming growth factor (TGF)-beta 1 for 24 hours before experiments. VEGF production was determined by enzyme-linked immunosorbent assay. Isolated hearts from adult male Sprague-Dawley rats were subjected to 15 minutes of equilibration, 25 minutes of ischemia, and 40 minutes reperfusion. Hearts (n = 5-7 per group) were randomly infused with vehicle, untreated MSCs, or MSCs pretreated with IL-1 beta and/or TGF-beta 1. Specific inhibitors were used to delineate the roles of 1)38 mitogen-activated protein kinase (MAPK) and SMAD3 in IL-1 beta- and TGE-beta 1-mediated stimulation of MSCs. Results. MSCs cotreated with IL-1 beta and TGF-beta 1 exhibited synergistically increased VEGF secretion, and they greatly improved postischemic myocardial functional recovery. Ablation of p38 MAPK and SMAD3 activation with specific inhibitors negated both IL-1 beta- and TGF-beta 1 mediated VEGF production in MSCs and the ability of these pretreated MSCs to improve myocardial recovery after ischemia. Conclusion. Pretreating MSCs with 2 cytokines may be useful to fully realize the potential of cell-based therapies for ischemic tissues. (Surgery 2012;151:353-63.)