IGF-1-Overexpressing Mesenchymal Stem Cells Accelerate Bone Marrow Stem Cell Mobilization via Paracrine Activation of SDF-1α/CXCR4 Signaling to Promote Myocardial Repair

We hypothesized that mesenchymal stem cells (MSCs) overexpressing insulin-like growth factor (IGF)-1 showed improved survival and engraftment in the infarcted heart and promoted stem cell recruitment through paracrine release of stromal cell-derived factor (SDF)-1 alpha. Rat bone marrow-derived MSCs were used as nontransduced ((MSCs)-M-Norm) or transduced with adenoviral-null vector ((MSCs)-M-Null) or vector encoding for IGF-1 (IGF-1MSCs). IGF-1MSCs secreted higher IGF-1 until 12 days of observation (P < 0.001 versus (MSCs)-M-Null). Molecular studies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl. xL and inhibition of glycogen synthase kinase 3 beta besides release of SDF-1 alpha in parallel with IGF-1 expression in IGF-1MSCs. For in vivo studies, 70 mu L of DMEM without cells (group 1) or containing 1.5 x 10(6) (MSCs)-M-Null (group 2) or IGF-1MSCs (group 3) were implanted intramyocardially in a female rat model of permanent coronary artery occlusion. One week later, immunoblot on rat heart tissue (n = 4 per group) showed elevated myocardial IGF-1 and phospho-Akt in group 3 and higher survival of IGF-1MSCs (P < 0.06 versus (MSCs)-M-Null) (n = 6 per group). SDF-1 alpha was increased in group 3 animal hearts (20-fold versus group 2), with massive mobilization and homing of ckit(+), MDR1(+), CD31(+), and CD34(+) cells into the infarcted heart. Infarction size was significantly reduced in cell transplanted groups compared with the control. Confocal imaging after immunostaining for myosin heavy chain, actinin, connexin-43, and von Willebrand factor VIII showed extensive angiomyogenesis in the infarcted heart. Indices of left ventricular function, including ejection fraction and fractional shortening, were improved in group 3 as compared with group 1 (P < 0.05). In conclusion, the strategy of IGF-1 transgene expression induced massive stem cell mobilization via SDF-1 alpha signaling and culminated in extensive angiomyogenesis in the infarcted heart. (Circ Res. 2008; 103: 1300-1308.)