Cardiovascular Research Advance Access originally published online on April 8, 2008
Cardiovascular Research 2008 79(3):405-415; 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, 3755 Cote Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2
2 Montreal Heart Institute, Université de Montréal, 5000, Bélanger Street East, Montréal, Quebéc, Canada H1T 1C8
3 Université du Québec à Montréal, Montréal, Quebéc, Canada
* Corresponding author. Tel: +1 514 376 3330; fax: +1 514 593 2575 (A.D.)/Tel: +1 514 340 8214; fax: +1 514 340 8281 (J.G.). E-mail address: a_ducharme{at}icm-mhi.com (A.D.)/jacques.galipeau{at}mcgill.ca (J.G.)
Aims: Mesenchymal stromal cells (MSCs) possess intrinsic features that identify them as useful for treating ischaemic 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 and results: MSCs from C57Bl/6 mice were retrovirally transduced with either an empty vector or one that causes the production of Epo and were then analysed for the alterations in angiogenic and survival potential. Using a mouse model of myocardial infarction (MI), the regenerative potential of null MSCs and Epo-overexpressing MSCs (Epo+MSCs) was assessed using serial echocardiogram and invasive haemodynamic measurements. Infarct size, capillary density and neutrophil influx were assessed using histologic techniques. 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 [wild-type (WT)-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 MI, animals receiving intracardiac injections of Epo+MSCs exhibited significantly enhanced cardiac function compared with WT-MSCs and saline-injected control animals post-MI, owing to the increased myocardial capillary density and the reduced neutrophilia.
Conclusion: Epo overexpression enhances the cellular regenerative properties of MSCs by both autocrine and paracrine pathways.
KEYWORDS Mesenchymal stromal cells; Erythropoietin; Angiogenesis; Cell therapy; Cardiovascular regeneration
Time for primary review: 23 days
These authors contributed equally.
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