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Mesenchymal stromal cells overexpressing vascular endothelial growth factor in ovine myocardial infarction

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Abstract

Mesenchymal stromal cells (MSCs) are cardioprotective in acute myocardial infarction (AMI). Besides, we have shown that intramyocardial injection of plasmid-VEGF165 (pVEGF) in ovine AMI reduces infarct size and improves left ventricular (LV) function. We thus hypothesized that MSCs overexpressing VEGF165 (MSCs-pVEGF) would afford greater cardioprotection than non-modified MSCs or pVEGF alone. Sheep underwent an anteroapical AMI and, 1 week later, received intramyocardial MSCs-pVEGF in the infarct border. One month post treatment, infarct size (magnetic resonance) decreased by 31% vs pre-treatment. Of note, myocardial salvage occurred predominantly at the subendocardium, the myocardial region displaying the largest contribution to systolic performance. Consistently, LV ejection fraction recovered to almost its baseline value because of marked decrease in end-systolic volume. None of these effects were observed in sheep receiving non-transfected MSCs or pVEGF. Although myocardial retention of MSCs decreased steeply over time, the treatment induced significant capillary and arteriolar proliferation, which reduced subendocardial fibrosis. We conclude that in ovine AMI, allogeneic VEGF-overexpressing MSCs induce subendocardial myocardium salvage through microvascular proliferation, reducing infarct size and improving LV function more than non-transfected MSCs or the naked plasmid. Importantly, the use of a plasmid rather than a virus allows for repeated treatments, likely needed in ischemic heart disease.

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Acknowledgements

We thank veterinarians María Inés Besansón and Pedro Iguain for anesthetic management and animal house assistants Juan Carlos Mansilla, Osvaldo Sosa and Juan Ocampo for dedicated care of the animals. We also thank Julio Martínez and Fabián Gauna for technical help. This study was supported by grants from the National Agency for the Promotion of Science and Technology (ANPCyT), Ministry of Science, Technology and Innovative Production (MINCyT) of Argentina.

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Authors and Affiliations

  1. Department of Physiology, Favaloro University, Buenos Aires, Argentina

    P Locatelli, F D Olea, A Hnatiuk & A Crottogini

  2. Favaloro Foundation University Hospital, Buenos Aires, Argentina

    A De Lorenzi, M Cerdá & C S Giménez

  3. Department of Pathology, Favaloro University, Buenos Aires, Argentina

    D Sepúlveda & R Laguens

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  1. P Locatelli
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Correspondence to A Crottogini.

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Locatelli, P., Olea, F., Hnatiuk, A. et al. Mesenchymal stromal cells overexpressing vascular endothelial growth factor in ovine myocardial infarction. Gene Ther 22, 449–457 (2015). https://doi.org/10.1038/gt.2015.28

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