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(Circulation Research. 2008;103:1300.)
© 2008 American Heart Association, Inc.

Cellular Biology

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, Shujia Jiang, Niagara M. Idris, Muhammad Ashraf

From the Department of Pathology and Laboratory Medicine, University of Cincinnati, Ohio.

Correspondence to Prof Muhammad Ashraf, Department of Pathology and Laboratory of Medicine, 231 Albert Sabin Way, University of Cincinnati, Cincinnati, OH 45267-0529. 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 3β 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 1.5x10^{6 Null}MSCs (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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