Abstract 1744: Ultrasound-induced Stimulation Of Microbubbles Augments And Targets Myocardial Engraftment Of Mesenchymal Stem Cells In Vivo
Background - Transplantation of mesenchymal stem cells (MSCs) is an approach to improve myocardial function in non-ischemic and ischemic cardiomyopathy. Both, efficacy and targeting of myocardial engraftment of MSCs are crucial variables. Overall, sustained myocardial cell therapy is a complex process depending on a timely and spatially orchestrated interplay between MSCs, endothelium and extracellular proteases. However, recruitment and engraftment of stem cells to the myocardium is limited. Thus, a strategy to enhance and to target sustained engraftment is of major interest. We tested whether ultrasound-mediated microbubble stimulation (UMS) not only allows focussed alteration of myocardial tissue, but also targeted enhancement of MSC engraftment.
Methods and Results - In part, WISTAR rats received anterolateral ischemia/reperfusion four days before transplantation of fluorescently labelled MSCs. Animals were exposed to UMS focussed on the anterior left-ventricular wall in vivo followed by intracoronary transplantation of MSCs in isolated heart perfusion or via aortic root catheter in vivo. Global and regional myocardial engraftment of MSCs was quantified distinguishuing endothelial adhesion, transendothelial migration and invasion of basement membrane by means of confocal laser-scanning microscopy. Moreover, impact of UMS on extracellular matrix proteases was assessed. Absolute myocardial MSC count and transendothelial migration were increased after UMS in both, non-ischemic and ischemic myocardium. Targeted segments exhibited higher cell count versus non-targeted tissue. Rate of transendothelial migration was lowest in non-ischemic (22.5 ± 2.9%) as compared to ischemic myocardium (35 ± 7.1%, p < 0.001). UMS significantly increased transmigration to 35 ± 4.1% (p < 0.001) and 51.2 ± 4.8% (p < 0.001), respectively. Additionally, myocardial segments exposed to UMS revealed onset of protease activity. Signs of fatal bioeffects, such as induction of apoptosis and/or myocardial necrosis were not observed.
Conclusions - This is the first evidence of transendothelial migration of MSCs in vivo. Focussed UMS not only augments targeted attraction but also improves engraftment of MSCs in non-ischemic and ischemic myocardium.