Transplantation of human neural stem cells protect against ischemia in a preventive mode via hypoxia-inducible factor-1alpha stabilization in the host brain

• Published in: Brain research 2008-05, Vol.1207, p.182-192
• Main Authors: Chu, Kon, Jung, Keun-Hwa, Kim, Se-Jeong, Lee, Soon-Tae, Kim, Juhyun, Park, Hee-Kwon, Song, Eun-Cheol, Kim, Seung U, Kim, Manho, Lee, Sang Kun, Roh, Jae-Kyu
• Format: Article
• Language: English
• Subjects: Animals; Brain - metabolism; Brain - surgery; Brain Infarction - prevention & control; Brain Ischemia - pathology; Brain Ischemia - prevention & control; Brain Ischemia - surgery; Chemokine CXCL12 - pharmacology; Cyclooxygenase 2 - metabolism; Deferoxamine - pharmacology; Disease Models, Animal; Dose-Response Relationship, Drug; Flow Cytometry - methods; Gene Expression Regulation - drug effects; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - drug effects; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Neurons - drug effects; Neurons - physiology; Rats; Receptors, CXCR4 - metabolism; Siderophores - pharmacology; Stem Cell Transplantation - methods; Stem Cells - drug effects; Stem Cells - physiology; Time Factors; Up-Regulation - physiology; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0006-8993
• DOI: 10.1016/j.brainres.2008.02.043

Hypoxia-inducible factor-1 (HIF-1) plays important roles in the prevention of cerebral ischemia. Deferoxamine (DFX), an iron chelator stabilizes the HIF-1alpha and activates target genes involved in compensation for ischemia. In this study, we are to investigate whether HIF-1alpha can be stabilized in human neural stem cells (NSCs) by DFX, and pre-transplantation of NSCs with HIF-1alpha stabilization can induce prolonged ischemic tolerance. In the DFX-treated NSCs, the HIF-1alpha protein expression was increased about 100-fold time-dependently, and subsequent transcriptional activation (VEGF, BDNF and CXCR4) was also observed. To test an ability to induce ischemic prevention in vivo, DFX-treated NSCs or naïve NSCs were transplanted in the striatum of adult rats. Seven days following the transplantation, focal cerebral ischemia was done. Infarct volumes were reduced in both NSCs-transplanted groups, compared with ischemia-only, but more reduced in DFX-treated NSCs group. The protective effects of NSCs were ablated when HIF-1alpha was silenced. HIF-1alpha protein levels were increased in both NSCs-transplanted groups, but more increased in DFX-treated NSCs group. RT-PCR analysis manifested a downregulation of mRNA expression of TNF-alpha, IL-6 and MMP-9 in both NSCs groups, but further decrease in DFX-treated NSCs group. These findings provide evidence that HIF-1alpha stabilization in human NSCs can be achieved effectively by DFX, and HIF-1alpha-stabilized NSCs protect against ischemia in a preventive mode.