title: Interleukin 6-preconditioned neural stem cells reduce ischaemic injury in stroke mice.
abstract: Transplantation of neural stem cells provides a promising therapy for stroke. Its efficacy, however, might be limited because of massive grafted-cell death after transplantation, and its insufficient capability for tissue repair. Interleukin 6 is a pro-inflammatory cytokine involved in the pathogenesis of various neurological disorders. Paradoxically, interleukin 6 promotes a pro-survival signalling pathway through activation of signal transducer and activator of transcription 3. In this study, we investigated whether cellular reprogramming of neural stem cells with interleukin 6 facilitates the effectiveness of cell transplantation therapy in ischaemic stroke. Neural stem cells harvested from the subventricular zone of foetal mice were preconditioned with interleukin 6 in vitro and transplanted into mouse brains 6 h or 7 days after transient middle cerebral artery occlusion. Interleukin 6 preconditioning protected the grafted neural stem cells from ischaemic reperfusion injury through signal transducer and activator of transcription 3-mediated upregulation of manganese superoxide dismutase, a primary mitochondrial antioxidant enzyme. In addition, interleukin 6 preconditioning induced secretion of vascular endothelial growth factor from the neural stem cells through activation of signal transducer and activator of transcription 3, resulting in promotion of angiogenesis in the ischaemic brain. Furthermore, transplantation of interleukin 6-preconditioned neural stem cells significantly attenuated infarct size and improved neurological performance compared with non-preconditioned neural stem cells. This interleukin 6-induced amelioration of ischaemic insults was abolished by transfecting the neural stem cells with signal transducer and activator of transcription 3 small interfering RNA before transplantation. These results indicate that preconditioning with interleukin 6, which reprograms neural stem cells to tolerate oxidative stress after ischaemic reperfusion injury and to induce angiogenesis through activation of signal transducer and activator of transcription 3, is a simple and beneficial approach for enhancing the effectiveness of cell transplantation therapy in ischaemic stroke.
authors.affiliation: Neurosurgical Laboratories, Stanford University, Stanford, CA 94305-5487, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakata
authors.forename: Purnima
authors.initials: P
authors.lastname: Narasimhan
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Niizuma
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Maier
authors.forename: Takuma
authors.initials: T
authors.lastname: Wakai
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000187:drug effects* / Q000637:transplantation*; D009460:Neurologic Examination / Q000379:methods / Q000706:statistics & numerical data; D034741:RNA, Small Interfering / Q000494:pharmacology; D020127:Recovery of Function / Q000187:drug effects*; D015427:Reperfusion Injury / Q000188:drug therapy; D050796:STAT3 Transcription Factor / Q000502:physiology; D020521:Stroke / Q000503:physiopathology / Q000628:therapy*; D013482:Superoxide Dismutase / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D043925:Angiogenesis Inducing Agents; D015850:Interleukin-6; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D013482:Superoxide Dismutase; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C494087:Stat3 protein, mouse