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.