title: Novel therapeutic strategy for stroke in rats by bone marrow stromal cells and ex vivo HGF gene transfer with HSV-1 vector.
abstract: Occlusive cerebrovascular disease leads to brain ischemia that causes neurological deficits. Here we introduce a new strategy combining mesenchymal stromal cells (MSCs) and ex vivo hepatocyte growth factor (HGF) gene transferring with a multimutated herpes simplex virus type-1 vector in a rat transient middle cerebral artery occlusion (MCAO) model. Gene-transferred MSCs were intracerebrally transplanted into the rats' ischemic brains at 2 h (superacute) or 24 h (acute) after MCAO. Behavioral tests showed significant improvement of neurological deficits in the HGF-transferred MSCs (MSC-HGF)-treated group compared with the phosphate-buffered saline (PBS)-treated and MSCs-only-treated group. The significant difference of infarction areas on day 3 was detected only between the MSC-HGF group and the PBS group with the superacute treatment, but was detected among each group on day 14 with both transplantations. After the superacute transplantation, we detected abundant expression of HGF protein in the ischemic brain of the MSC-HGF group compared with others on day 1 after treatment, and it was maintained for at least 2 weeks. Furthermore, we determined that the increased expression of HGF was derived from the transferred HGF gene in gene-modified MSCs. The percentage of apoptosis-positive cells in the ischemic boundary zone (IBZ) was significantly decreased, while that of remaining neurons in the cortex of the IBZ was significantly increased in the MSC-HGF group compared with others. The present study shows that combined therapy is more therapeutically efficient than MSC cell therapy alone, and it may extend the therapeutic time window from superacute to acute phase.
authors.affiliation: Department of Neurosurgery, Osaka Medical College, Takatsuki, Osaka, Japan.
authors.forename: Ming-Zhu
authors.initials: MZ
authors.lastname: Zhao
authors.forename: Naosuke
authors.initials: N
authors.lastname: Nonoguchi
authors.forename: Naokado
authors.initials: N
authors.lastname: Ikeda
authors.forename: Takuji
authors.initials: T
authors.lastname: Watanabe
authors.forename: Daisuke
authors.initials: D
authors.lastname: Furutama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Miyazawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Funakoshi
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Kajimoto
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Mari
authors.initials: M
authors.lastname: Dezawa
authors.forename: Masa-Aki
authors.initials: MA
authors.lastname: Shibata
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Otsuki
authors.forename: Robert S
authors.initials: RS
authors.lastname: Coffin
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Liu
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kuroiwa
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Miyatake
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016026:Bone Marrow Transplantation / Q000379:methods*; D001921:Brain / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D018259:Herpesvirus 1, Human / Q000235:genetics*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D020768:Middle Cerebral Artery / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000473:pathology / Q000628:therapy*; D017154:Stromal Cells / Q000637:transplantation*; D016896:Treatment Outcome
chemical_list: D017228:Hepatocyte Growth Factor