Transplantation of genetic modified stem cells over-expressing therapeutic growth factors for the treatment of experimental rat myocardial infarction

We tested the hypothesis that simultaneous transgenic overexpression of a select quartet of growth factors activates diverse signaling pathways for mobilization and participation of various stem/progenitor cells for cardiogenesis in the infarcted heart. IGF-1, VEGF, SDF-1α, and HGF plasmids were synthesized and transfected into rat skeletal myoblasts (SM). Overexpression of growth factors in transfected SM (TransSM) was confirmed by reverse transcription PCR, western blotting, and fluorescence immunostaining. The conditioned medium (CM) from TransSM was cytoprotective for cardiomyocytes following H 2O 2 treatment, promoted a higher transwell migration of HUVEC cells and in vitro tube formation. Intramyocardial transplantation of 1.5×10 6 TransSM in a rat model of acute myocardial infarction induced extensive mobilization of stem/progenitor cells into the infarcted heart on day 7 and improved integration of TransSM in the heart compared to NatSM. Extensive neomyogenesis and angiogenesis with resultant attenuation of infarct size and improvement in global heart function was observed at 8 weeks. In conclusion, simultaneous activation of diverse signaling pathways by overexpression of multiple growth factors caused massive mobilization and homing of stem/progenitor cells from peripheral circulation, the bone marrow, and the heart for accelerated repair of the infarcted myocardium.