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(Circulation. 2009;119:2587-2596.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Sca-1⁺ Stem Cell Survival and Engraftment in the Infarcted Heart

Dual Role for Preconditioning-Induced Connexin-43

Gang Lu, MD, PhD; Husnain K. Haider, MPharm, PhD; Shujia Jiang, MD; Muhammad Ashraf, PhD

From the Department of Pathology and Laboratory Medicine, 231 Albert Sabin Way, University of Cincinnati, Cincinnati, Ohio.

Correspondence to Professor Muhammad Ashraf, Department of Pathology and Laboratory Medicine, 231 Albert Sabin Way, University of Cincinnati, Cincinnati, OH 45267-0529. E-mail ashrafm{at}ucmail.uc.edu

Received October 14, 2008; accepted March 20, 2009.

Background— We report that elevated connexin-43 (Cx-43) in stem cells preconditioned with insulin-like growth factor-1 (IGF-1) is cytoprotective and reprograms the cells for cardiomyogenic differentiation.

Methods and Results— Sca-1⁺ cells were preconditioned with 100 nmol/L IGF-1 for 30 minutes followed by 8 hours of oxygen glucose deprivation to assess the cytoprotective effects of preconditioning. LDH release assay, cytochrome c release, and mitochondrial membrane potential assay showed improved survival of preconditioned Sca-1⁺ cells under oxygen glucose deprivation compared with nonpreconditioned Sca-1⁺ cells via PI3K/Akt-dependent caspase-3 downregulation. We observed PI3K/Akt-dependent upregulation of cardiac-specific markers including MEF-2c (2.5-fold), GATA4 (3.1-fold), and Cx-43 (3.5-fold). Cx-43 inhibition with specific RNA interference reduced cell survival under oxygen glucose deprivation and after transplantation. In vivo studies were performed in a female rat model of acute myocardial infarction (n=78). Animals were grouped to receive intramyocardially 70 µL Dulbecco modified Eagles medium without cells (group 1) or containing male 1x10⁶ nonpreconditioned Sca-1⁺ cells (group 2) or preconditioned Sca-1⁺ (group 3) cells labeled with PKH26. Survival of the preconditioned Sca-1⁺ cells was 5.5-fold higher in group 3 compared with group 2 at 7 days after transplantation. Confocal imaging after actinin and Cx-43 specific immunostaining showed extensive engraftment and myogenic differentiation of preconditioned Sca-1⁺ cells. Compared with group 2, group 3 showed increased blood vessel density (22.3±1.7 per microscopic field; P<0.0001) and attenuated infarction size (23.3±3.6%; P=0.002). Heart function indices including ejection fraction (56.2±3.5; P=0.029) and fractional shortening (24.3±2.1; P=0.03) were improved in group 3 compared with group 2.

Conclusions— Preconditioning with IGF-1 reprograms Sca-1⁺ for prosurvival signaling and cardiomyogenic differentiation with an important role for Cx-43 in this process.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2009 119: 2537-2538. [Extract] [Full Text]

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