Cardiovascular Research Advance Access [Accepted Manuscript] published online on April 8, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn090
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Coupling erythropoietin secretion to mesenchymal stromal cells enhances their regenerative properties
1 Sir Mortimer B. Davis Jewish General Hospital (McGill University)
2 Montreal Heart Institute (Université de Montréal)
3 Université du Québec à Montréal
** Contact Information for Corresponding Authors: Jacques Galipeau, MD FRCP(C) Sir Mortimer B. Davis Jewish General Hospital (McGill University) 3755 Cote Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2 Tel: 514 340 8214, Fax: 514 340 8281 jacques.galipeau{at}mcgill.ca
** Anique Ducharme, MD, MSc FRCP(C) Montreal Heart Institute (Université de Montréal) 5000, Bélanger Street East, Montréal, Quebéc, Canada H1T 1C8 Tel: 514 376 3330, Fax: 514 593 2575 a_ducharme{at}icm-mhi.com
Aims: Mesenchymal stromal cells (MSCs) possess intrinsic features that identify them as useful for treating ischemic syndromes. Poor in vivo survival/engraftment of MSCs, however limits their overall effectiveness. In this work we tested whether genetically engineering MSCs to secrete erythropoietin (Epo) could represent a better therapeutic platform than MSCs in their native form.
Methods: MSCs from C57Bl/6 mice were retrovirally transduced with either an empty vector or one that causes the production of erythropoietin and were then analyzed for alterations in angiogenic and survival potential. Using a mouse model of myocardial infarction, the regenerative potential of null MSCs and Epo+MSCs were assessed using serial echocardiogram and invasive hemodynamic measurements. Assessment of infarct size, capillary density and neutrophil influx was assessed using histologic techniques.
Results: Using in vitro assays coupled with an in vivo Matrigel plug assay, we demonstrate that engineering MSCs to express Epo does not alter their immunophenotype or plasticity. However, relative to mock-modified MSCs (WT-MSCs), Epo-overexpressing MSCs (Epo+MSCs) are more resilient to apoptotic stimuli and initiate a more robust host-derived angiogenic response. We also identify and characterize the autocrine loop established on MSCs by having them secrete Epo. Furthermore, in a murine model of myocardial infarction (MI), animals receiving intracardiac injections of Epo+MSCs exhibited significantly enhanced cardiac function compared to WT-MSCs and saline-injected control animals post-MI, owing to increased myocardial capillary density and reduced neutrophilia.
Conclusion: Epo overexpression enhances the cellular regenerative properties of MSCs by both autocrine and paracrine pathways.
Time for primary review: 23 days
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Cardiovasc Res 2008 79: 357-359.
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