Regenerative cellular therapy: Positive remodeling after myocardial infarction using iv injected mesenchymal stem cells and cytokine enhancement

Introduction: Adult mesenchymal stem cell (MSC)-based treatment strategies have been proposed to alleviate the consequences of myocardial infarction (MI). Methods and Results: Mice underwent LAD ligation. Cytokine enhancement (CE) of HGF or VEGF by intramyocardial injection at the time of MI significantly facilitated MSC homing (11±4 and 7±4, respectively, vs. 1±0.5 cells/HPF without CE; p=0.001). Cardiac geometry and function was monitored over 6 months using ECG-triggered Micro-CTs. 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 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 to 33.2±2% and 34.4±7%, respectively. Differentation of MSCs into cardiomyocyte-like cells was not observed. Conclusion: 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.