Erythropoietin (Epo) Secreting Mesenchymal Stromal Cells and Autocrine Signalling Via the Epo Receptor. A Novel, Cell-Based Paracrine Epo Delivery System for Cardiovascular Therapy.

Abstract

Separately, the roles of MSCs and erythropoietin (Epo) in cardiovascular regenerative therapy have expanded rapidly. However, poor in vivo survival/engraftment of MSCs and Epo's short half-life and bioavailability, limit their individual effectiveness. We propose that a combinatorial approach would be synergisitic. We therefore determined whether administration of Epo-secreting Mesenchymal stromal cells (MSCs) could represent a better therapeutic platform in cardiovascular medicine than MSCs in their primeval form. MSCs from C57Bl/6 mice were retrovirally transduced to express murine Epo (Epo+MSCs) and compared to wild type (WT) MSCs in relation to their abilities to promote positive heart tissue remodelling following myocardial infarction (MI). Relative to WT-MSCs, we found that via an Epo/EpoR autocrine loop, Epo+MSCs have an enhanced proliferative capacity and are more resilient to apoptotic stimuli. In vivo, Epo+MSCs also have enhanced survival and can initiate a more robust host-derived angiogenic response. Injection of WT-MSCs or Epo+MSCs into the borderzone of the MI following ligation of the left coronary artery demonstrated engraftment within the borderzone seven days post-implantation, while sequential (7 and 14 day post-MI) echocardiograms and invasive hemodynamic measurements (14 days post-MI) showed that the Epo+MSC group exhibited significantly improved LV systolic and diastolic function compared to WT-MSCs injected animals and PBS controls (Fractional shortening 29.7% ± 8.5 versus 19.9% ± 6.6 and 19.1% ± 7.4 respectively, p=0.02). Myocardial capillary density was significantly higher in the Epo+MSC group and was coupled to reduced neutrophilic infiltration by direct actions of Epo on endothelial and neutrophil chemotaxis. In conclusion, we show that Epo overexpression enhances the cellular regenerative properties of MSCs by both autocrine and paracrine pathways.