Published online before print October 23, 2008, doi: 10.1161/CIRCRESAHA.108.186742
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Submitted on July 23, 2008
Revised on October 8, 2008
Accepted on October 9, 2008
IGF-1–Overexpressing Mesenchymal Stem Cells Accelerate Bone Marrow Stem Cell Mobilization via Paracrine Activation of SDF-1
/CXCR4 Signaling to Promote Myocardial Repair
Husnain Kh Haider ;
From the Department of Pathology and Laboratory Medicine, University of Cincinnati, Ohio.
* To whom correspondence should be addressed. E-mail: muhammad.ashraf{at}uc.edu.
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
. 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 3
besides release of SDF-1 in parallel with IGF-1 expression in IGF-1MSCs. For in vivo studies, 70 µL of DMEM without cells (group 1) or containing 1.5x106 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-1 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 signaling and culminated in extensive angiomyogenesis in the infarcted heart.
Key words: IGF-1 • heart • myocardial infarction • SDF-1
•
stem cells
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