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The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert pleiotropic effects on cardiac cell biology which are not yet fully understood. Here we tested whether statin treatment affects resident endogenous cardiac stem/progenitor cell (CSC) activation in vitro and in vivo after myocardial infarction (MI). Statins (Rosuvastatin, Simvastatin and Pravastatin) significantly increased CSC expansion in vitro as measured by both BrdU incorporation and cell growth curve. Additionally, statins increased CSC clonal expansion and cardiosphere formation. The effects of statins on CSC growth and differentiation depended on Akt phosphorylation. Twenty-eight days after myocardial infarction by permanent coronary ligation in rats, the number of endogenous CSCs in the infarct border zone was significantly increased by Rosuvastatin-treatment as compared to untreated controls. Additionally, commitment of the activated CSCs into the myogenic lineage (c-kitpos/Gata4pos CSCs) was increased by Rosuvastatin administration. Accordingly, Rosuvastatin fostered new cardiomyocyte formation after MI. Finally, Rosuvastatin treatment reversed the cardiomyogenic defects of CSCs in c-kit haploinsufficient mice, increasing new cardiomyocyte formation by endogenous CSCs in these mice after myocardial infarction. In summary, statins, by sustaining Akt activation, foster CSC growth and differentiation in vitro and in vivo. The activation and differentiation of the endogenous CSC pool and consequent new myocyte formation by statins improve myocardial remodeling after coronary occlusion in rodents. Similar effects might contribute to the beneficial effects of statins on human cardiovascular diseases.

This work presents a disposable passive microfluidic system, allowing chemotaxis studies, through the generation of a concentration gradient. The device can handle liquid flows without an external supply of pressure or electric gradients, but simply using gravity force. It is able to ensure flow rates of 10 &micro, L/h decreasing linearly with 2.5% in 24 h. The device is made of poly(methylmethacrylate) (PMMA), a biocompatible material, and it is fabricated by micro-milling and solvent assisted bonding. It is assembled into a mini incubator, designed properly for cell biology studies in passive microfluidic devices, which provides control of temperature and humidity levels, a contamination-free environment for cells with air and 5% of CO2. Furthermore, the mini incubator can be mounted on standard inverted optical microscopes. By using our microfluidic device integrated into the mini incubator, we are able to evaluate and follow in real-time the migration of any cell line to a chemotactic agent. The device is validated by showing cell migration at a rate of 0.36 &micro, m/min, comparable with the rates present in scientific literature.