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

Background and Purpose - 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.