Hypoxia-specific GM-CSF-overexpressing neural stem cells improve graft survival and functional recovery in spinal cord injury.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine that stimulates the differentiation and function of hematopoietic cells. GM-CSF has been implicated in nervous system function. The goal of the present study was to understand the effects of hypoxia-induced GM-CSF on neural stem cells (NSCs) in a model of spinal cord injury (SCI). GM-CSF-overexpressing NSCs were engineered utilizing a hypoxia-inducible gene expression plasmid, including an Epo enhancer ahead of an SV promoter (EpoSV-GM-CSF). Cells were then subjected to hypoxia (pO(2), 1%) or a hypoxia-mimicking reagent (CoCl(2)) in vitro. The progression of time of GM-CSF expression was tracked in EpoSV-GM-CSF-transfected NSCs. Overexpression of GM-CSF in undifferentiated and differentiated NSCs created resistance to H(2)O(2)-induced apoptosis in hypoxia. NSCs transfected with EpoSV-GM-CSF or SV-GM-CSF were transplanted into rats after SCI to assess the effect of GM-CSF on NSC survival and restoration of function. Moreover, a significantly higher amount of surviving NSCs and neuronal differentiation was observed in the EpoSV-GM-CSF-treated group. Significant improvement in locomotor function was also found in this group. Thus, GM-CSF overexpression by the Epo enhancer in hypoxia was beneficial to transplanted NSC survival and to behavioral improvement, pointing toward a possible role for GM-CSF in the treatment of SCI.
Spine and Spinal Cord Institute, Department of Neurosurgery, Yonsei University College of Medicine, Seoul, South Korea.
H J
HJ
Kim
J S
JS
Oh
S S
SS
An
W A
WA
Pennant
S-J
SJ
Gwak
A N
AN
Kim
P K
PK
Han
D H
DH
Yoon
K N
KN
Kim
Y
Y
Ha
D000818:Animals; D015687:Cell Hypoxia; D004742:Enhancer Elements, Genetic; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D018014:Gene Transfer Techniques; D006085:Graft Survival; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D008297:Male; D058953:Neural Stem Cells / Q000378:metabolism / Q000637:transplantation*; D010957:Plasmids; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013539:Simian virus 40 / Q000235:genetics*; D013119:Spinal Cord Injuries / Q000628:therapy*
D004921:Erythropoietin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor