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

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 (shRNA ) and subjected to simulated ischemia/reoxygenation in vitro. Both sildenafil and shRNA PDE-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 3 10 5 ) 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 cell transplantation as a therapy for cardiac fibrosis

“…The in vivo effect was also associated with increased vascular density and decreased cardiac fibrosis. Overall, the protective effect of modified cells was suggested to be due to increased duration and release of paracrine factors in the ischaemic myocardium [62]. Figure 1 summarizes the effects of stem cell modifications on cardiac fibrosis following MI.…”

Advances in the research of basic study and clinical application of adipose-derived mesenchymal stem cells

“…For example, sildenafil or short hairpin RNA was used for preprocessing to inhibit ADSC to express phosphodiesterase 5, which improved the therapeutic effect of intramyocardial injection of ADSC after myocardial infarction in mice. [65] 5 Cell-free therapy…”

The role of the microenvironment on the fate of adult stem cells

“…For example, studies have now shown that MSC protein extracts or con- ditioned medium collected from MSC cultures can produce many of the same beneficial effects as MSCs on the post-infarction heart and in damaged liver tissues [69,70]. MSCs appear to secrete VEGF and basic fibroblast growth factor (bFGF) upon contacting the injured myocardium, which stimulates the formation of new vessels and increases the capillary density to increase/restore blood flow to the infarcted region [71]. However, the secretory activity of MSCs strongly depends on their tissue microenvironmental conditions.…”