Preconditioning by Phosphodiesterase-5 Inhibition Improves Therapeutic Efficacy of Adipose-Derived Stem Cells Following Myocardial Infarction in Mice§

Authors

  • Nicholas N. Hoke,

    1. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
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  • Fadi N. Salloum,

    1. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
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  • David A. Kass,

    1. Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
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  • Anindita Das,

    1. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
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  • Rakesh C. Kukreja

    Corresponding author
    1. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
    • Pauley Heart Center, Division of Cardiology, Box 980204, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-020D, Richmond, Virginia 23298, USA
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    • Telephone: 804-628-5521; Fax: 804-828-8700


  • Author contributions: N.H.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; F.S.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; D.K.: provision of study material; A.D.: conception and design, data analysis and interpretation, and manuscript writing; R.K.: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS November 18, 2011.

Abstract

The rationale of this article is enhancing the therapeutic potential of stem cells in ischemic microenvironments by novel preconditioning strategies is critical for improving cellular therapy. We tested the hypothesis that inhibition of phosphodiesterase-5 (PDE-5) with sildenafil (Viagra) or knockdown with a silencing vector in adipose-derived stem cells (ASCs) would improve their survival and enhance cardiac function following myocardial implantation in vivo. ASCs were treated with sildenafil or PDE-5 silencing vector short hairpin RNA (shRNAPDE-5) and subjected to simulated ischemia/reoxygenation in vitro. Both sildenafil and shRNAPDE-5 significantly improved viability, decreased necrosis, apoptosis, and enhanced the release of growth factors, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), and insulin-like growth factor. Inhibition of protein kinase G reversed these effects. To show the beneficial effect of preconditioned ASCs in vivo, adult male CD-1 mice underwent myocardial infarction. Preconditioned ASCs (4 × 105) were directly injected intramyocardially. Preconditioned ASC-treated hearts showed consistently superior cardiac function when compared with nonpreconditioned ASCs after 4 weeks of treatment. This was associated with significantly reduced fibrosis, increased vascular density, and decreased resident myocyte apoptosis when compared with mice receiving nonpreconditioned ASCs. VEGF, b-FGF, and Angiopoietin-1 were also significantly elevated 4 weeks after cell therapy with preconditioned ASCs. We conclude that preconditioning by inhibition of PDE-5 can be a powerful novel approach to improve stem cell therapy following myocardial infarction. STEM CELLS 2012; 30:326–335.

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