Transplantation of neural stem cells expressing hypoxia-inducible factor-1alpha (HIF-1alpha) improves behavioral recovery in a rat stroke model.
We explored the possibility that hypoxia-inducible factor-1alpha (HIF-1alpha) might contribute to the therapeutic effect of neural stem cell (NSC) transplantation in cerebral ischemia. The relative efficacy of modified NSC to promote behavioral recovery was investigated in a rat model of stroke induced by a transient middle cerebral artery occlusion (MCAO). A recombinant adenovirus (Ad-HIF-1alpha) was engineered to express HIF-1alpha. Control NSC infected with control adenovirus (NSC-Ad), recombinant adenovirus Ad-HIF-1alpha, or NSC infected by Ad-HIF-1alpha (NSC-Ad-HIF-1alpha), were used for intraventricular transplantion into rat brain 24 hours after MCAO. Neurological deficits were assessed over 4 weeks using the modified neurological severity scale (NSS) score. Long-term in vivo expression of HIF-1alpha was demonstrated by Western blotting and immunocytochemistry, and derivatives of nestin-positive transplanted cells contributed to both neuronal (neurofilament-positive) and astroglial (glial fibrillary acidic protein-positive) lineages. All animals showed functional improvement. Improvement was accelerated in animals receiving either NSC-Ad or Ad-HIF-1alpha, while improvement at all times between 7 days and 28 days post MCAO was significantly greater in animals transplanted with NSC-Ad-HIF-1alpha than for other treated animals. NSC-Ad-HIF-1alpha cells also increased the number of factor VIII-positive cells in the region of ischemic injury, indicating that HIF-1alpha expression can promote angiogenesis. Gene-modified NSC expressing HIF-1alpha have therapeutic potential in ischemic stroke.
Wu
Wanfu
W
Department of Neurology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Chen
Xiu
X
Hu
Changlin
C
Li
Jinfang
J
Yu
Zhen
Z
Cai
Wenqin
W
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D016380:Brain Tissue Transplantation / Q000379:methods*; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006085:Graft Survival / Q000502:physiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D020521:Stroke / Q000235:genetics / Q000378:metabolism* / Q000601:surgery*; D014162:Transfection / Q000379:methods; D016896:Treatment Outcome
D015415:Biomarkers; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit