Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells.
BACKGROUND
Hematopoietic cytokines, granulocyte colony-stimulating factor (G-CSF), and stem cell factor (SCF) were reported to show a neuroprotective effect or to support neurogenesis. These cytokines also mobilize bone marrow (BM) cells into the brain, and the BM-derived cells differentiate into neuronal cells. We administered these hematopoietic cytokines after focal cerebral ischemia and assessed their effects and the therapeutic time window for neuronal regeneration.


RESULTS
We induced permanent middle cerebral artery occlusion in mice whose BM had been replaced with BM cells from green fluorescent protein (GFP)-transgenic mice. The occluded mice were treated with G-CSF and SCF in the acute phase (days 1 to 10) or subacute phase (days 11 to 20), and the brain functions and histological changes were evaluated. Separately, we injected bromodeoxyuridine during cytokine treatment to assess cell kinetics in the brain. Six mice were prepared for each experimental group. Administration of G-CSF and SCF in the subacute phase effectively improved not only motor performance but also higher brain function, compared with acute-phase treatment. Acute-phase and subacute-phase treatments identically reduced the infarct volume relative to vehicle treatment. However, subacute-phase treatment significantly induced transition of BM-derived neuronal cells into the peri-infarct area and stimulated proliferation of intrinsic neural stem/progenitor cells in the neuroproliferative zone.


CONCLUSIONS
Administration of G-CSF and SCF in the subacute phase after focal cerebral ischemia is effective for functional recovery, enhancing cytokine-induced generation of neuronal cells from both BM-derived cells and intrinsic neural stem/progenitor cells. Because G-CSF and SCF are available for clinical use, these findings suggest a new therapeutic strategy for stroke.
Kawada
Hiroshi
H
Division of Hematology, Department of Medicine, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, Japan. hkawada@is.icc.u-tokai.ac.jp
Takizawa
Shunya
S
Takanashi
Tomomi
T
Morita
Yuko
Y
Fujita
Jun
J
Fukuda
Keiichi
K
Takagi
Shigeharu
S
Okano
Hideyuki
H
Ando
Kiyoshi
K
Hotta
Tomomitsu
T
D000818:Animals; D001854:Bone Marrow Cells; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002544:Cerebral Infarction / Q000188:drug therapy*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D016298:Hematopoietic Cell Growth Factors / Q000008:administration & dosage*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods; D020244:Infarction, Middle Cerebral Artery; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology*; D019089:Stem Cell Factor / Q000008:administration & dosage; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D016896:Treatment Outcome
D016298:Hematopoietic Cell Growth Factors; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor