Coupling erythropoietin secretion to mesenchymal stromal cells enhances their regenerative properties.
OBJECTIVE
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.


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.


CONCLUSIONS
Epo overexpression enhances the cellular regenerative properties of MSCs by both autocrine and paracrine pathways.
Copland
Ian B
IB
Sir Mortimer B. Davis Jewish General Hospital, McGill University, 3755 Cote Ste-Catherine Road, Montreal, Quebec, Canada H3T 1E2.
Jolicoeur
E Marc
EM
Gillis
Marc-Antoine
MA
Cuerquis
Jessica
J
Eliopoulos
Nicoletta
N
Annabi
Borhane
B
Calderone
Angelo
A
Tanguay
Jean-Francois
JF
Ducharme
Anique
A
Galipeau
Jacques
J
D000818:Animals; D017209:Apoptosis; D019898:Autocrine Communication; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D020556:Neutrophil Infiltration; D019899:Paracrine Communication; D012038:Regeneration; D017154:Stromal Cells / Q000378:metabolism / Q000637:transplantation*; D014161:Transduction, Genetic; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
D004921:Erythropoietin