Efficacy of the coadministration of granulocyte colony-stimulating factor and stem cell factor in the activation of intrinsic cells after spinal cord injury in mice.
OBJECTIVE
Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine that induces undifferentiated stem cells from the bone marrow (BM) into the peripheral blood. Stem cell factor (SCF) is also a hematopoietic cytokine that stimulates the differentiation and proliferation of neural stem cells and has neuroprotective effects. In cerebrally infarcted mice, the combination of G-CSF and SCF promotes the differentiation of BM-derived cells into neural cells, stimulates the proliferation of intrinsic neural stem cells, and improves motor function. The object of this study was to investigate the effects of these cytokines on BM stem cells, intrinsic cells, and motor function recovery in spinal cord-injured mice.


METHODS
For marking BM-derived cells, the authors induced contusive spinal cord injury in mice transplanted with BM cells from green fluorescent protein (GFP)-transgenic mice after whole-body irradiation. These mice were treated with G-CSF and SCF in the subacute injury phase. Bromodeoxyuridine (BrdU) was injected into these mice to label proliferating cells. The cell numbers and phenotype of the BM-derived cells were evaluated, and the change in intrinsic cells (proliferation, accumulation, and differentiation) was noted using immunohistological analysis at 4 weeks postinjury (wpi). A behavior analysis was conducted until 12 wpi using the Basso, Beattie, Bresnahan locomotor rating scale.


RESULTS
In the SCF + G-CSF group, improvement in hindlimb motor function was significantly greater than in the SCF group, G-CSF group, and sham-treatment (vehicle) group after 8 wpi. At 4 wpi, the number of GFP+ BM-derived cells induced in the lesion did not significantly differ between groups. At 4 wpi, the authors evaluated perilesional GFP− intrinsic spinal cord cells. The number of GFP− and F4/80+ cells was significantly greater in the SCF + G-CSF group than in the other 3 groups. As compared with the sham group, the number of NG2+/BrdU+ cells was significantly increased in the SCF + G-CSF group.


CONCLUSIONS
In this study, the combined administration of SCF and G-CSF in traumatic spinal cord injury not only improved motor function, but also induced the accumulation of intrinsic microglia and the active proliferation of intrinsic oligodendrocyte precursor cells.
Osada
Takahiro
T
Department of Neurosurgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Watanabe
Masahiko
M
Hasuo
Atsuhiro
A
Imai
Masaaki
M
Suyama
Kaori
K
Sakai
Daisuke
D
Kawada
Hiroshi
H
Matsumae
Mitsunori
M
Mochida
Joji
J
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects*; D016026:Bone Marrow Transplantation; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D004338:Drug Combinations; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006614:Hindlimb / Q000503:physiopathology; D007275:Injections, Intravenous; D049408:Luminescent Agents / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology; D010641:Phenotype; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000503:physiopathology*; D019089:Stem Cell Factor / Q000008:administration & dosage*; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
D004338:Drug Combinations; D049408:Luminescent Agents; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D049452:Green Fluorescent Proteins