S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Neurology (신경과학교실) Journal Papers (저널논문_신경과학교실)
Transplantation of human neural stem cells protect against ischemia in a preventive mode via hypoxia-inducible factor-1alpha stabilization in the host brain
- 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
- Issue Date
- Brain Res. 1207, 182-192
- Animals; Brain/metabolism/surgery; Brain Infarction/prevention & control; Brain Ischemia/pathology/prevention & control/*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/*metabolism; Neurons/drug effects/*physiology; Rats; Receptors, CXCR4/metabolism; Siderophores/pharmacology; Stem Cell Transplantation/*methods; Stem Cells/drug effects/*physiology; Time Factors; Up-Regulation/physiology; Vascular Endothelial Growth Factor A/metabolism
- 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 naive 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.
- 0006-8993 (Print)
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