Transduction of human EPO into human bone marrow mesenchymal stromal cells synergistically enhances cell-protective and migratory effects.
Human bone marrow mesenchymal stromal cells (hBM-MSCs) are a promising tools for cell therapy. However, the poor viability of the transplanted cells is a major limiting factor. Human erythropoietin (hEPO) has been extensively studied in non-hematopoietic tissues for its neurotrophic, anti-oxidant, anti-apoptotic, and antiinflammatory effects. In this study, we evaluate whether transduction of the hEPO gene into MSCs provides protection and affects their migration. hBM-MSCs transduced with the hEPO gene (EPO-MSCs) stably secreted high levels of hEPO (10 IU/ml) with no alteration of their mesenchymal phenotype. MSCs were also treated with 10 IU rhEPO, an amount similar to what was secreted by EPO-MSCs, to generate 10U-MSCs. Protection against H2O2-induced oxidative stress and staurosporine-induced apoptosis was registered for both EPO-MSCs and 10U-MSCs, but the protective effects were higher for the EPO-MSCs than for the 10U-MSCs. EPO-MSCs had significantly higher migration rates compared to MSCs and 10U-MSCs. We confirmed that the intracellular signaling of ERK1/2 was higher in the EPO-MSCs than 10U-MSCs. This data demonstrates that the endogenous expression of EPO may efficiently initiate the ERK1/2 signaling pathway, resulting in synergistic effects on the production of neurotrophic factors. Thus, EPO-MSCs are a good candidate for cell therapy in ischemic and neurodegenerative diseases.
Kim
Mi-Hwa
MH
Department of Neurology, Hanyang University College of Medicine, Seoul, Korea. kimsh1@hanyang.ac.kr
Cho
Goang-Won
GW
Huh
Yong-Min
YM
Kim
Seung Hyun
SH
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D014161:Transduction, Genetic
D004791:Enzyme Inhibitors; D016877:Oxidants; D004921:Erythropoietin; D006861:Hydrogen Peroxide; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019311:Staurosporine