Bone marrow stromal cells that enhanced fibroblast growth factor-2 secretion by herpes simplex virus vector improve neurological outcome after transient focal cerebral ischemia in rats.
OBJECTIVE
Fibroblast growth factor-2 (FGF-2) administration and bone marrow stromal cell (MSC) transplantation could improve neurological deficits after occlusive cerebrovascular disease. In the present study, we examined the effects of neurological improvement after transient middle cerebral artery occlusion (MCAO) in rats by a novel therapeutic strategy with FGF-2 gene-transferred MSCs by the herpes simplex virus type 1 (HSV-1) vector.


METHODS
Adult Wistar rats were anesthetized. Nonmodified MSCs, FGF-2-modified MSCs with HSV-1 1764/-4/pR19/ssIL2-FGF-2, or PBS was administered intracerebrally 24 hours after transient right MCAO. All animals underwent behavioral tests for 21 days, and the infarction volume with 2-3-5-triphenylterazolium was detected 3 days and 14 days after the MCAO. Three days and 7 days after the MCAO, the FGF-2 production in the ipsilateral hemisphere of the MCAO was measured with ELISA. Seven and 14 days after the MCAO, immunohistochemical staining for FGF-2 was applied.


RESULTS
The stroke animals receiving FGF-2-modified MSCs demonstrated significant functional recovery compared with the other groups. Fourteen days after the MCAO, there was a significant reduction in infarction volume only in FGF-2-modified MSC-treated group. FGF-2 production in the FGF-2-modified MSC-treated brain was significantly higher compared with the other groups at 3 and 7 days after MCAO. Administrated FGF-2-modified MSCs strongly expressed the FGF-2 protein, which was proven by ELISA.


CONCLUSIONS
Our data suggest that the FGF-2 gene-modified MSCs with the HSV-1 vector can contribute to remarkable functional recovery after stroke compared with MSCs transplantation alone.
Ikeda
Naokado
N
Department of Neurosurgery, Osaka Medical College, Japan.
Nonoguchi
Naosuke
N
Zhao
Ming Zhu
MZ
Watanabe
Takuji
T
Kajimoto
Yoshinaga
Y
Furutama
Daisuke
D
Kimura
Fumiharu
F
Dezawa
Mari
M
Coffin
Robert S
RS
Otsuki
Yoshinori
Y
Kuroiwa
Toshihiko
T
Miyatake
Shin-Ichi
S
D000818:Animals; D016026:Bone Marrow Transplantation; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology*; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D017154:Stromal Cells / Q000637:transplantation*; D014020:Tissue Extracts / Q000378:metabolism
D014020:Tissue Extracts; D016222:Fibroblast Growth Factor 2