Abstract 1096: Cytokine Enhancement with Hgf Or Vegf in the Infarct Border Zone is Key to Attenuating the Negative Remodelling after Myocardial Infarction
Adult mesenchymal stem cell (MSC)-based treatment strategies have been proposed to alleviate the consequences of myocardial infarction (MI). The cytokine release of ischemic myocardium was investigated in vivo after LAD ligations in mice and in vitro in cultured cardiomyocytes. Of all cytokines that were at least 5-fold upregulated during ischemia, only HGF and VEGF proved to promote MSC proliferation, and chemotaxis in vitro. Homing of intranenously (IV) injected MSCs (0.5×106 per animal) into the infarct border zone after LAD ligation was inefficient (1±0.5 cells/HPF). Cytokine enhancement (CE) of HGF or VEGF by intramyocardial injection at the time of MI significantly facilitated MSC homing (11±4 cells/HPF and 7±4 cells/HPF, respectively; p=0.001). To our knowledge, this is the first study monitoring cardiac geometry and function over a long-term period of 6 months. using ECG-triggered contrast Micro-CT. It revealed that the progressive decrease in EF over time (to 19±1%) could be attenuated by CE with HGF (29±6%; p=0.003) or VEGF (28±4%; p=0.004) and subsequent IV MSC injection. However, LVEFs of animals treated with CE with HGF or VEGF only, but received no MSC injection, were similar to those groups that also received IV MSCs (p=0.127 and p=0.54, respectively). Best results were finally achieved by prolonged presence of HGF or VEGF, achieved by intramyocardial injection of MSCs stably transfected to produce HGF or VEGF and firefly luciferase into the infarct border zone. Duration of cytokine release was estimated by monitoring MSC survival using in vivo bioluminescence imaging (BLI). BLI signals were detectable for 10 days in contrast to the rapid fate of the cytokines after single dose administration in the CE group, resulting in preserved LVEFs at 6 months This study highlights the beneficial effect of HGF and VEGF to attenuate the negative LV remodelling after MI and diminishes the role of the MSCs to a pure delivery system for paracrine effects.