Transplantation of human neural stem cells protect against ischemia in a preventive mode via hypoxia-inducible factor-1alpha stabilization in the host brain.
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.
Chu
Kon
K
Stroke and Neural Stem Cell Laboratory in Clinical Research Institute, Department of Neurology, Seoul National University Hospital, Seoul, South Korea.
Jung
Keun-Hwa
KH
Kim
Se-Jeong
SJ
Lee
Soon-Tae
ST
Kim
Juhyun
J
Park
Hee-Kwon
HK
Song
Eun-Cheol
EC
Kim
Seung U
SU
Kim
Manho
M
Lee
Sang Kun
SK
Roh
Jae-Kyu
JK
D000818:Animals; D001921:Brain / Q000378:metabolism / Q000601:surgery; D020520:Brain Infarction / Q000517:prevention & control; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control / Q000601:surgery*; D054377:Chemokine CXCL12 / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003676:Deferoxamine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism; D017262:Siderophores / Q000494:pharmacology; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4; D017262:Siderophores; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D003676:Deferoxamine