Combined Therapeutic Strategy Using Erythropoietin and Mesenchymal Stem Cells Potentiates Neurogenesis after Transient Focal Cerebral Ischemia in Rats

Abstract

Many studies showed beneficial effects of either erythropoietin (EPO) or mesenchymal stem cells (MSCs) treatment in cerebral ischemia. In addition to a neuroprotective role, not only EPO but also MSC favors neurogenesis and functional recovery. In an attempt to further improve postischemic tissue repair, we investigated the effect of a systemic administration of MSC, in the presence or not of EPO, on neurogenesis and functional recovery in a transient focal cerebral ischemia model in the adult rat. Twenty-four hours after ischemia, the rats were divided into four groups, namely vehicle, MSC, EPO, and MSC + EPO, and received a single intravenous injection of MSC (2¾10 6 cells) and/or a repeated intraperitoneal administration of EPO (1,000 UI/kg) for 3 days. The lesion volume, the MSC outcome, neurogenesis, and functional recovery were assessed 51 days after ischemia. The results showed that cellular proliferation and neurogenesis were increased along the lateral ventricle wall in the MSC + EPO group, whereas no significant effect was observed in groups receiving MSC or EPO alone. This effect was accompanied by an improvement of mnesic performances. Mesenchymal stem cells expressing neuronal or glial markers were detected in the ischemic hemisphere. These results suggest that EPO could act in a synergistic way with MSC to potentiate the postischemic neurogenesis.

Survival, neuron-like differentiation and functionality of mesenchymal stem cells in neurotoxic environment: the critical role of erythropoietin

“…14 It also abolishes hypoxia-induced death of neuronal progenitors in vitro 15 and acts synergistically with MSC to potentiate the post-ischemic neurogenesis in a rat model of cerebral ischemia. 16 Although these findings support a pivotal role of EPO in neuroprotection, the mechanisms of its beneficial influence on therapeutic cells (e.g., MSC) remain unclear. Taking into consideration that MSC engrafted into neurodegenerative tissue will be exposed to hypoxia (either caused by surgery or initially present as a pathogenetic factor of the respective disease) and Glu excess (caused by the disease), in this study we investigated the influence of EPO on the survival, differentiation and protective features of MSC exposed to hypoxia, Glu and Abeta.…”

Extended and stable gene expression via nucleofection of MIDGE construct into adult human marrow mesenchymal stromal cells

“…While high concentrations of recombinant EPO could be administered intravenously to enable some protein to reach the injured sites, there are also risks of thrombosis and hypertension to be considered (Baskin and Lasker 1990;Ghezzi and Brines 2004;Lieutaud et al 2008;Loo and Beguin 1999). Local delivery of EPO by MSC has manifested a more potent therapeutic effect for treatment of myocardium infarct (Copland et al 2008) and cerebral ischemia (Esneault et al 2008) than with delivery of MSC or EPO alone in in vivo studies. EPO could trigger the phosphorylation of Janus associated kinase 2 (JAK2) and thus enhance the survivability of MSC in hypoxic tissue (Mangi et al 2003;Rossert and Eckardt 2005).…”

Mesenchymal stem cell–mediated ectopic hematopoiesis alleviates aging-related phenotype in immunocompromised mice

“…29 A promising combined therapeutic modality using EPO and mesenchymal stem cells has been suggested in the neurogenesis of ischemic cerebral injury in rats. 30 In this study, we uncovered a potentially clinical impact in delaying the aging process using the innate physiologic process of bone marrow-mediated stem cell renewal and differentiation. Our model of subcutaneous transplantation of BMMSC using a carrier provides a long-term engraftment of BMMSCs at the ectopic site at least 18 months, and these BMMSCs can be transferred to new hosts by secondary transplantation.…”