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

Abstract

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 comparedwith 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

Combined Therapeutic Strategy Using Erythropoietin and Mesenchymal Stem Cells Potentiates Neurogenesis after Transient Focal Cerebral Ischemia in Rats

“…Furthermore, MSCs have shown efficiency as therapeutic vectors. Indeed, these cells, genetically modified to overexpress, for example, brain-derived neurotrophic factor (Kurozumi et al, 2004;Nomura et al, 2005), glial cell line-derived neurotrophic factor (Kurozumi et al, 2005), and fibroblast growth factor (Ikeda et al, 2005), were therapeutically more efficient than nonmodified MSC. Recently, a study reported beneficial effects of combined treatments, that is bone marrow cells and adenovirus overexpressing metalloproteinase inhibitors (Baker et al, 2007).…”

Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury

“…59 The potential benefits of FGF2 are supported by studies showing that gene-transfected MSCs expressing this growth factor demonstrated improved functional recovery after stroke compared with MSC transplantation alone. 60 Ex vivo gene transfer has also been attempted with hepatocyte growth factor (HGF) which resulted in decreased apoptosis, increased neuron survival in the ischemic boundary zone and functional improvement. 61 …”

Hypoxia-Inducible Factor 1-α-AA-Modified Bone Marrow Stem Cells Protect PC12 Cells from Hypoxia-Induced Apoptosis, Partially Through VEGF/PI3K/Akt/FoxO1 Pathway

“…Many studies on stroke using BMSCs as treatment suggest genetic modification of BMSCs to improve therapeutic potential. Indeed, overexpression of trophic factors such as brain-derived neurotrophic factor (BDNF), fibroblast growth factor-2, and hematopoietic growth factor in gene-modified BMSCs has been demonstrated to improve neurologic outcome in animal models of ischemic stroke [7][8][9] Hypoxia-inducible factor-1 (HIF-1) is an oxygen-sensitive transcription factor [10]. HIF-1 is a heterodimeric protein that consists of a functional HIF-1a subunit and a constitutively expressed HIF-1b subunit.…”