Ex Vivo VEGF Delivery by Neural Stem Cells Enhances Proliferation of Glial Progenitors, Angiogenesis, and Tissue Sparing after Spinal Cord Injury 英文参考文献.docVIP

ExVivoVEGFDeliverybyNeuralStemCellsEnhances ProliferationofGlialProgenitors,Angiogenesis,and TissueSparingafterSpinalCordInjury HyukMinKim1,DongHoonHwang1,JongEunLee3,SeungU.Kim4,5,ByungG.Kim1,2 * 1BrainDiseaseResearchCenter,InstituteforMedicalSciences,AjouUniversitySchoolofMedicine,Suwon,Korea,2DepartmentofNeurology,AjouUniversitySchoolof Medicine, Suwon, Korea, 3Department of Anatomy, BK21 Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea, 4Division of Neurology, DepartmentofMedicine,UniversityofBritishColumbia,Vancouver,Canada,5MedicalResearchInstitute,ChungangUniversitySchoolofMedicine,Seoul,Korea Abstract Thepresentstudywasundertakentoexaminemultifacetedtherapeuticeffectsofvascularendothelialgrowthfactor(VEGF) inaratspinalcordinjury(SCI)model,focusingonitscapabilitytostimulateproliferationofendogenousglialprogenitor cells. Neural stem cells (NSCs) can be genetically modified to efficiently transfer therapeutic genes to diseased CNS. We adoptedanexvivoapproachusingimmortalizedhumanNSCline(F3cells)toachievestableandrobustexpressionofVEGF intheinjuredspinalcord.TransplantationofNSCsretrovirallytransducedtooverexpressVEGF(F3.VEGFcells)at7daysafter contusiveSCImarkedlyelevatedtheamountofVEGFintheinjuredspinalcordtissuecomparedtoinjectionofPBSorF3 cells without VEGF. Concomitantly, phosphorylation of VEGF receptor flk-1 increased in F3.VEGF group. Stereological counting of BrdU+ cells revealed that transplantation of F3.VEGF significantly enhanced cellular proliferation at 2 weeks afterSCI.ThenumberofproliferatingNG2+glialprogenitorcells(NG2+/BrdU+)wasalsoincreasedbyF3.VEGF.Furthermore, transplantation of F3.VEGF increased the number of early proliferating cells that differentiated into mature oligodendrocytes,butnotastrocytes,at6weeksafterSCI.F3.VEGFtreatmentalsoincreasedthedensityofbloodvessels in the injured spinal cord and enhanced tissue sparing. These anatomical results were accompanied by improved BBB locomotorscores.Themul