IGF-1–overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1α/CXCR4 signaling to promote …

HK Haider, S Jiang, NM Idris, M Ashraf - Circulation research, 2008 - Am Heart Assoc
Circulation research, 2008Am Heart Assoc
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)-1α. Rat bone marrow–derived MSCs were used as nontransduced (NormMSCs) or
transduced with adenoviral-null vector (NullMSCs) or vector encoding for IGF-1 (IGF-
1MSCs). IGF-1MSCs secreted higher IGF-1 until 12 days of observation (P< 0.001 versus …
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)-1α. Rat bone marrow–derived MSCs were used as nontransduced (NormMSCs) or transduced with adenoviral-null vector (NullMSCs) or vector encoding for IGF-1 (IGF-1MSCs). IGF-1MSCs secreted higher IGF-1 until 12 days of observation (P<0.001 versus NullMSCs). Molecular studies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl.xL and inhibition of glycogen synthase kinase 3β besides release of SDF-1α in parallel with IGF-1 expression in IGF-1MSCs. For in vivo studies, 70 μL of DMEM without cells (group 1) or containing 1.5×106 NullMSCs (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 NullMSCs) (n=6 per group). SDF-1α 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-1α signaling and culminated in extensive angiomyogenesis in the infarcted heart.
Am Heart Assoc