VASCULAR ENDOTHELIAL GROWTH FACTOR GENE-TRANSFERRED BONE MARROW STROMAL CELLS ENGINEERED WITH A HERPES SIMPLEX VIRUS TYPE 1 VECTOR CAN IMPROVE NEUROLOGICAL DEFICITS AND REDUCE INFARCTION VOLUME IN RAT BRAIN ISCHEMIA

Abstract

Several reports recently suggested that vascular endothelial growth factor (VEGF) may have a therapeutic benefit against experimental cerebral infarction animal models. In addition, bone marrow stromal cells (BMSCs) are known to have therapeutic potency in improving neurological deficits after occlusive cerebrovascular diseases. In the present study, we evaluated the hypothesis that intracerebral transplantation of VEGF gene-transferred BMSCs could provide a greater therapeutic effect than intracerebral transplantation of native (non-gene-transformed) BMSCs by using a transient middle cerebral artery occlusion (MCAO) rat model. Adult Wistar rats (Japan SLC, Inc., Hamamatsu, Japan) were anesthetized. VEGF gene-transferred BMSCs engineered with a replication-deficient herpes simplex virus type 1 1764/4-/pR19-hVEGF165 vector, native BMSCs, or phosphate-buffered saline were administered intracerebrally 24 hours after transient MCAO. All animals underwent behavioral testing for 28 days, and the infarction volume was determined 14 days after MCAO. The brain water contents in the ipsilateral and contralateral hemispheres of the MCAO were measured 2 and 7 days after the MCAO. Fourteen days after MCAO, immunohistochemical staining for VEGF was performed. The group receiving VEGF-modified BMSCs demonstrated significant functional recovery compared with those receiving native BMSCs. Fourteen days after the MCAO, there was a significantly lower infarct volume without aggravating cerebral edema in the group treated with VEGF gene-modified BMSCs compared with the control groups. The transplanted VEGF gene-modified BMSCs strongly expressed VEGF protein for at least 14 days. Our data suggest that the intracerebral transplantation of VEGF gene-transferred BMSCs may provide a more potent autologous cell transplantation therapy for stroke than the transplantation of native BMSCs alone.