Basic Investigation
Mesenchymal Stem Cells Pretreatment With Stromal-Derived Factor-1 Alpha Augments Cardiac Function and Angiogenesis in Infarcted Myocardium

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Abstract

Background

Stem cell therapy is among the novel approaches for the treatment of post-myocardial infarction cardiomyopathy. This study aims to compare the effect of stromal-derived factor 1 α (SDF1α), mesenchymal stem cells (MSCs) in combination with the lentiviral production of vascular endothelial growth factor (VEGF) on infarct area, vascularization and eventually cardiac function in a rat model of myocardial infarction (MI).

Methods

The influence of SDf1α on MSCs survival was investigated. MSCs were transduced via a lentiviral vector containing VEGF. After that, the effect of mesenchymal stem cell transfection of VEGF-A165 and SDf1α preconditioning on cardiac function and scar size was investigated in five groups of MI rat models. The MSC survival, cardiac function, scar size, angiogenesis, and lymphocyte count were assessed 72 hours and 6 weeks after cell transplantation.

Results

SDF1α decreased the lactate dehydrogenase release in MSCs significantly. Also, the number of viable cells in the SDF1α-pretreated group was meaningfully more than the control. The left ventricular systolic function significantly enhanced in groups with p240MSC, SDF1αMSC, and VEGF-A165MSC in comparison to the control group.

Conclusions

These findings suggest that SDF1α pretreatment and overexpressing VEGF in MSCs could augment the MSCs' survival in the infarcted myocardium, reduce the scar size, and improve the cardiac systolic function.

Introduction

Ischemic heart disease is the leading cause of mortality and morbidity worldwide. Recent remarkable advances in reperfusion of patients with acute myocardial infarction (MI) lead to decreased mortality of such patients. Although state-of-the-art medicines are developed to manage patients with post-MI heart failure, they cannot restore the lost myocardial function due to cardiomyocyte necrosis. Hence, there is still an enormous demand to find new approaches to manage patients with post-MI heart failure. Mesenchymal stem cells (MSCs) demonstrate promising potential to treat patients with post-MI heart failure. These cells are used alone or in combination with different growth factors and chemokines to improve the efficiency of treatment.1,2 Among the variety of such mediators, vascular endothelial growth factor-A (VEGF-A) and stromal-derived factor-1 alpha (SDF1α) show the most promising results in preclinical studies.3, 4, 5, 6, 7, 8, 9 Although all preclinical VEGF-A experiments and even small clinical trials eventuated positive effects on cardiac function, the positive impact of its combination with SDF1α as a strategy to enhance the survival of MSCs in the ischemic area and as a stem cell recruiting factor on injured myocardium is still somehow controversial.10,11 Previous studies tested the efficacy of different combinations of VEGF-A and SDF1α and different routes of administration, including stem cell preconditioning, systemic administration, and direct myocardial injection. Moreover, various studies applied different treatment periods, cell types, and transfer methods.12,13 The current study aimed at investigating the possible effect of VEGF-A expressing MSCs with and without adjuvant treatment with SDF1α on cardiac systolic function, infarct size, and neovascularization in a rat model of MI.

Section snippets

Materials and methods

All the procedures were based on the National Institutes of Health guide for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978) and the ethical standards of the animal research approved by the Iranian Ministry of Health and Medical Education.

MSC characterization

Adipogenic, osteogenic and chondrogenic differentiation of MSCs was confirmed by staining with Oil Red O and Alizarin Red S and Alcian Blue staining. Osteogenic and differentiation was also confirmed by alkaline phosphatase assay. The differentiation assays proved that the isolated MSCs had the potential to be differentiated into osteoblasts and adipocytes. Alizarin Red S staining and alkaline phosphatase level confirmed osteogenic differentiation. Oil Red O staining showed lipid vacuoles in

Discussion

Despite the great advances to overcome cardiac complications, especially myocardial infarction, most of the newly introduced medications and techniques failed to eliminate MI as a major challenge. Recent studies on stem cells, various genes, and growth factors are accounted for a large portion of the research efforts in this respect in the past years. The current study aimed at considering the impact of MSCs expressing the VEGF-A gene along with SDF1α pretreatment as a strategy to enhance the

Conclusions

The current study aimed at evaluating the impact of a combination of gene and cell therapies on cardiac function, scar size, and neovascularization in rats with post-MI systolic heart failure. It was observed that using MSCs alone or together with the SDF1α or with SDF1α and VEGF-A gene improved cardiac function, reduced scar size, and increased the peri-infarct capillary density. The combination of MSC, SDF1 α, and VEGF-A have the best result. Furthermore, pretreatment of MSCs with SDF1α

Acknowledgements

None.

Conflicts of Interest

None.

Source of Funding

The current study was financially supported by the Iranian Council of Stem Cell Technology (grant number: F574).

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