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Neural stem cells modified by a hypoxia-inducible VEGF gene expression system improve cell viability under hypoxic conditions and spinal cord injury

 Hong Lian Jin  ;  William A. Pennant  ;  Yoon Ha  ;  Do Heum Yoon  ;  Keung Nyun Kim  ;  Joon Cho  ;  Jin Soo Oh  ;  Meng Lu Liu  ;  Hyun Ah Kim  ;  Sung Su An  ;  Min Hyung Lee 
 Spine, Vol.36(11) : 857-864, 2011 
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STUDY DESIGN: An in vitro neural hypoxia model and rat spinal cord injury (SCI) model were used to assess the regulation of therapeutic vascular endothelial growth factor (VEGF) gene expression in mouse neural stem cells (mNSCs) by the EPO (erythropoietin) enhancer or RTP801 promoter. OBJECTIVE: To increase VEGF gene expression in mNSCs under hypoxic conditions in SCI lesions but avoid unwanted overexpression of VEGF in normal sites, we developed a hypoxia-inducible gene expression system consisting of the EPO enhancer and RTP801 promoter fused to VEGF or the luciferase gene, then transfected into mNSCs. SUMMARY OF BACKGROUND DATA: On the basis of the ischemic response in the injured area, poor cell survival at the transplantation site is a consistent problem with NSC transplantation after SCI. Although VEGF directly protects neurons and enhances neurite outgrowth, uncontrolled overexpression of VEGF in uninjured tissue may cause serious adverse effects. To effectively improve NSC survival in ischemic sites after transplantation, we evaluated mNSCs modified by a hypoxia-inducible VEGF gene expression system in an SCI model. METHODS: Hypoxia-inducible luciferase or VEGF plasmids were constructed using the EPO enhancer or RTP801 promoter. The effect of these systems on targeted gene expression and cell viability was evaluated in mNSCs in both hypoxic in vitro injury and a rat SCI model in vivo. RESULTS: The gene expression system containing the EPO enhancer or RTP801 promoter significantly increased the expression of the luciferase reporter gene and therapeutic VEGF gene under hypoxic conditions. The Epo-SV-VEGF plasmid transfection group had significantly fewer apoptotic cells in vitro. This system also augmented cell viability in the in vivo SCI model. CONCLUSION: These results strongly suggest the potential utility of mNSCs modified by a hypoxia-inducible VEGF gene expression system in the development of effective stem cell transplantation protocols in SCI.
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1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Medical Research Center (임상의학연구센터)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실)
Yonsei Authors
김긍년(Kim, Keung Nyun) ; 김홍련(Jin, Hong Lian) ; 안성수(An, Sung Su) ; 오진수(Oh, Jin Soo) ; 윤도흠(Yoon, Do Heum) ; 하윤(Ha, Yoon)
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