title: Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice.
abstract: Previous studies have shown that intraparenchymal transplantation of neural stem cells ameliorates neurological deficits in animals with intracerebral hemorrhage. However, hemoglobin in the host brain environment causes massive grafted cell death and reduces the effectiveness of this approach. Several studies have shown that preconditioning induced by sublethal hypoxia can markedly improve the tolerance of treated subjects to more severe insults. Therefore, we investigated whether hypoxic preconditioning enhances neural stem cell resilience to the hemorrhagic stroke environment and improves therapeutic effects in mice. To assess whether hypoxic preconditioning enhances neural stem cell survival when exposed to hemoglobin, neural stem cells were exposed to 5% hypoxia for 24 hours before exposure to hemoglobin. To study the effectiveness of hypoxic preconditioning on grafted-neural stem cell recovery, neural stem cells subjected to hypoxic preconditioning were grafted into the parenchyma 3 days after intracerebral hemorrhage. Hypoxic preconditioning significantly enhanced viability of the neural stem cells exposed to hemoglobin and increased grafted-cell survival in the intracerebral hemorrhage brain. Hypoxic preconditioning also increased neural stem cell secretion of vascular endothelial growth factor. Finally, transplanted neural stem cells with hypoxic preconditioning exhibited enhanced tissue-protective capability that accelerated behavioral recovery. Our results suggest that hypoxic preconditioning in neural stem cells improves efficacy of stem cell therapy for intracerebral hemorrhage.
authors.affiliation: Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Takuma
authors.initials: T
authors.lastname: Wakai
authors.affiliation: Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Purnima
authors.initials: P
authors.lastname: Narasimhan
authors.affiliation: Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakata
authors.affiliation: Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshioka
authors.affiliation: Department of Neurosurgery, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kinouchi
authors.affiliation: Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences, Stanford University School of Medicine, Stanford, California, USA phchan@stanford.edu.
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
mesh_terms: D000818:Animals; D002470:Cell Survival; D002543:Cerebral Hemorrhage / Q000628:therapy*; D006085:Graft Survival; D006454:Hemoglobins / Q000009:adverse effects / Q000378:metabolism; D000860:Hypoxia; D019194:Ischemic Preconditioning / Q000379:methods*; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism / Q000637:transplantation*; D020127:Recovery of Function; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D006454:Hemoglobins; D042461:Vascular Endothelial Growth Factor A
keywords: Cell transplantation therapy; hypoxic preconditioning; intracerebral hemorrhage; neural stem cells; vascular endothelial growth factor