title: Notch-induced rat and human bone marrow stromal cell grafts reduce ischemic cell loss and ameliorate behavioral deficits in chronic stroke animals.
abstract: Gene transfection with Notch 1 intracellular domain and subsequent growth factor treatment stimulate neuron-like differentiation of bone marrow stromal cells (BMSCs). Here, we examined the potential of transplanting Notch-induced BMSCs to exert therapeutic effects in a rat model of chronic ischemic stroke. In experiment 1, Notch-induced rat BMSCs were intrastriatally transplanted in rats at 1 month after being subjected to transient occlusion of middle cerebral artery (MCAo). Compared to post-stroke/pretransplantation level, significant improvements in locomotor and neurological function were detected in stroke rats that received 100 k and 200 k BMSCs, but not in those that received 40 k BMSCs. Histological results revealed 9%-15% graft survival, which dose-dependently correlated with behavioral recovery. At 5 weeks post-transplantation, some grafted BMSCs were positive for the glial marker GFAP (about 5%), but only a few cells (2-5 cells per brain) were positive for the neuronal marker NeuN. However, at 12 weeks post-transplantation, where the number of GFAP-positive BMSCs was maintained (5%), there was a dramatic increase in NeuN-positive BMSCs (23%). In experiment 2, Notch-induced human BMSCs were intrastriatally transplanted in rats at 1 month following the same MCAo model. Improvements in both locomotor and neurological function were observed from day 7 to day 28 post-transplantation, with the high dose (180 k) displaying significantly better behavioral recovery than the low dose (90 k) or vehicle. There were no observable adverse behavioral effects during this study period that also involved chronic immunosuppression of all animals. Histological analyses revealed a modest 5%-7% graft survival, with few (<1%) cells expressing an intermediate MAP2 neuronal marker, but not glial or oligodendroglial markers. In addition, striatal peri-infarct cell loss was significantly reduced in transplanted stroke animals compared to vehicle-treated stroke animals. The present study demonstrates the potential of Notch-induced BMSC cell therapy for patients presenting with fixed ischemic stroke.
authors.affiliation: Department of Neurology, Medical College of Georgia, Augusta, Georgia, USA.
authors.forename: Takao
authors.initials: T
authors.lastname: Yasuhara
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Matsukawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Hara
authors.forename: Mina
authors.initials: M
authors.lastname: Maki
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Ali
authors.forename: Seong Jin
authors.initials: SJ
authors.lastname: Yu
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Bae
authors.forename: Guolong
authors.initials: G
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.forename: Michael
authors.initials: M
authors.lastname: McGrogan
authors.forename: Krys
authors.initials: K
authors.lastname: Bankiewicz
authors.forename: Casey
authors.initials: C
authors.lastname: Case
authors.forename: Cesar V
authors.initials: CV
authors.lastname: Borlongan
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001854:Bone Marrow Cells / Q000166:cytology*; D001921:Brain / Q000473:pathology; D002470:Cell Survival; D002908:Chronic Disease; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000150:complications / Q000473:pathology* / Q000628:therapy; D008297:Male; D017072:Neostriatum / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000378:metabolism*; D020521:Stroke / Q000150:complications / Q000473:pathology / Q000628:therapy*; D017154:Stromal Cells / Q000166:cytology* / Q000637:transplantation*; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
chemical_list: D005904:Glial Fibrillary Acidic Protein; D051880:Receptors, Notch