Cardiovascular Research Advance Access first published online on September 22, 2007
This version [Corrected Proof] published online on December 4, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm025
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Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium
1 Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267-0529, USA
2 National Centre of Excellence in Molecular Biology, Punjab University, Lahore, Pakistan
* Corresponding author. Tel: +1 513 558 0145; fax: +1 513 558 0807. E-mail address: muhammad.ashraf{at}uc.edu
Aims: We hypothesized that preconditioning (PC) with stromal-derived factor 1 alpha (SDF-1) significantly enhances cell survival, proliferation, and engraftment of bone marrow-derived mesenchymal stem cells (MSCs) via SDF-1/CXCR4 signaling.
Methods and results: MSCs were cultured and then incubated in medium for 60 min without SDF-1 (control group) or with SDF-1 0.05 µg/mL (SDF-1 group) or CXCR4-selective antagonist, AMD 3100 (AMD) (5 µg/mL, AMD group) or SDF-1 and AMD (0.05 µg/mL, 5 µg/mL, respectively, SDF-1+AMD group). MSCs were treated for 60 min, washed in normal medium, and then exposed to H2O2 (100 µmol/L) for 60 min to determine the effects of various treatments on cell injury, viability, and proliferation. For in vivo studies, rats were grouped (n = 6) after left anterior descending coronary artery ligation to receive 20 µL Dulbecco’s modified Eagle’s medium without cells or with 5 x 105 non-preconditioned MSCs (control group), SDF-1 preconditioned MSCs (SDF-1 group), AMD (AMD group), or MSCs treated with SDF-1 plus AMD (SDF-1+AMD group). Heart function, infarct size, fibrosis, and MSC proliferation and differentiation in infarcted myocardium were determined after 4 weeks. In vitro data showed a marked increase in cell viability and proliferation following SDF-1 PC. In vivo data in preconditioned group showed a robust cell proliferation, reduction in infarct size and fibrosis, and significant improvement in cardiac function. Effects of SDF-1 PC were abrogated by CXCR4 antagonist.
Conclusion: We conclude that PC with the chemokine SDF-1 suppresses MSCs apoptosis, enhances their survival, engraftment, and vascular density, and improves myocardial function via SDF/CXCR4 signaling. Chemokine PC is a novel approach for enhancing stem cell survival and regeneration of infarcted myocardium.
KEYWORDS Preconditioning; Myoangiogenesis; Apoptosis; Infarction; Stromal-derived factor 1 alpha
Time for primary review 33 days
Both authors contributed equally to this work
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