The neuroprotective effect of erythropoietin-transduced human mesenchymal stromal cells in an animal model of ischemic stroke.
Erythropoietin (EPO) exhibits diverse cellular functions, including neurotrophic, anti-oxidant, anti-apoptotic, and anti-inflammatory effects in non-hematopoietic tissues. This study evaluated whether bone marrow mesenchymal stromal cells (MSCs) transduced with the EPO gene (EPO-MSCs) promoted neural cell survival and improved neurological deficits caused by ischemic stroke. EPO-MSCs stably produced high levels of EPO (10IU/ml) without any alteration of their mesenchymal phenotype. Both EPO transduction and treatment with 10 international units (IU) of recombinant human EPO (rhEPO) provided protection from H(2)O(2)-induced oxidative injury in human bone marrow mesenchymal stromal cells and in SH-SY5Y cells. EPO-MSCs were more protected than were MSCs treated with 10IU rhEPO (10U-MSCs). We also found that the expression of the neurotrophic factors BDNF, PD-ECGF, HGF, SDF-1alpha, and TGF-1beta increased in EPO-MSCs, while only BDNF and TGF-1beta increased in 10U-MSCs. Implantation of EPO-MSCs in an animal model of ischemic stroke significantly improved neurological function and decreased infarct volumes without affecting hematocrit level. An evaluation of the brain tissue 21days after implantation showed that EPO and phosphorylated Akt (a downstream mediator of EPO) increased only in brains implanted with EPO-MSCs. Transduction of the EPO gene into MSCs induced secretion of EPO and various trophic factors that may provide excellent neuroprotective effects in both in vitro and in vivo models of ischemic stroke.
Cho
Goang-Won
GW
Department of Neurology, College of Medicine, Hanyang University, Seongdong-gu, Seoul, Republic of Korea.
Koh
Seong-Ho
SH
Kim
Mi-Hwa
MH
Yoo
A Rum
AR
Noh
Min Young
MY
Oh
Sechul
S
Kim
Seung Hyun
SH
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000628:therapy*; D016086:Lentivirus / Q000502:physiology; D008279:Magnetic Resonance Imaging; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009422:Nervous System Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D018709:Statistics, Nonparametric; D013778:Tetrazolium Salts; D013844:Thiazoles; D014161:Transduction, Genetic / Q000379:methods
D015703:Antigens, CD; D009414:Nerve Growth Factors; D013778:Tetrazolium Salts; D013844:Thiazoles; D004921:Erythropoietin; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; D053148:Caspase 3; C022616:thiazolyl blue