1992 Reynolds Richards

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Βαριησού Κουταλιανός
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1 212 Basic Medical Sciences and Clinics (3) : ( 2002) ( ) : : ; ; :R :A (central nervous system [1 CNS) ] James Thomson John Gearhart (embryonic stem cells ES cells) ; [2 3 ] (peripheral nervous system PNS) CNS CNS [4 7 CNS ] ( 1) (stem cells) CNS CNS CNS? CNS CNS Reynolds Richards [8 9 ] ( neural stem cells NSCs) CNS ( 1989 ) CNS ( ) CNS CNS PNS CNS : : ( G ) 3

2002122 (3) Basic Medical Sciences and Clinics 213 2 [10 ] 1 Fig 1 Produced location of embryo and adult stem cell in central nervous system of human being CNS CNS : ( subven2 tricular zone SVZ)

2 (3) Basic Medical Sciences and Clinics [10 ] 1 Fig 1 Produced location of embryo and adult stem cell in central nervous system of human being CNS CNS : ( subven2 tricular zone SVZ) (subgran2 CNS ular zone SGZ) [11 ] SVZ (rostral migratory stream RMS) ;SGZ (epidermal growth factor EGF) ( basic fibroblast growth factor bfgf) [12 ] [13 NSC ] ( 1) 1998 Eriksson 2 4 [16 17 ] (S ) DNA 52 (52bro2 modeoxyuridine BrdU) Br2 [18 ] ; [14 du ] Johansson (neurospheres) [8 ] CNS ; [11 19 ] [15 ] CNS

3 214 Basic Medical Sciences and Clinics (3) 50 [20 ] CNS PΠT 1 :hgfp [27 (telomerase) ] ( neuroepithelial stem cell pro2 [21 ] tein nestin) mushashi1 (leukemia inhibitory factor LIF) nestin ( EΠnestin) mushashi1 ( PΠmushashi1) LIF (htert) GFP [22 ] PΠmushashi1 : v2myc large2t hgfp EΠnestin : EGFP HNSC1100 ; 40h ; [28 ] 3 [23 24 ] Nobuko 50 ( ) CD133 + Π CNS CD34 - ΠCD45 - [25 ] CD133 + [29 ] ; 62 (62OHDA) 1 % 6 % (TGF ) CD9 [30 ] CD15 CD81 CD95(Fas) GD2 [26 I(MHC2Class2I) 2 ] 90min SGZ SVZ ( GFP) [31 GFP ( EGFP) ] Goldman GFP 1 (PΠT 1) PΠT 1 CNS

4 (3) Basic Medical Sciences and Clinics 215 [32 ] [36 CNS ] CNS [33 ] 98 % western blot Nurr1 CNS [37 ] 4 CNS CNS CNS CNS PD 20 (Parkinson s disease PD) (Alzheimer s disease AD) (Huntington s disease HD) CNS PD [39 ] [40 ] PD [34 ] PD PD [39 ] CNS PD ; [37 IL2 ] 1 IL21 ( tyrosine 1999 Janet Fricker hydroxylase) (dopamine DA) (do2 Cedars2Sinai pa2decarboxylase DDC) (DA transport2 PD [38 ] PD er DAT) PD 2 IL2 1 IL211 ( Glail2derived neuro2 6 8 trophic factor GDNF) LIF Fluoro2DOPA PET [41 ] 20 % 25 % [35 ]

5 216 Basic Medical Sciences and Clinics (3) 5 [45 ] [46 ] CA1 90 % 95 % 1 % 3 3 % 9 % NeuN 120 ; [42 ] CNS CNS Benedetti IL24 GL261 6 CNS IL24 [43 ] (cytosine deaminase) [44 ] : [1 ] Temple S. The development of neural stem cells[j ]. Nature : [2 ] Thomson JA Itskovitz2Eldor J Shapiro SS et al. Embryonic stem cell lines derived from human blastocysts [J ]. Science : [3 ] Gearhart J. New potential for human embryonic stem cells[j ]. Science : [4 ] Doetsch F Caille I Lim DA et al. Subventricular zone astro2 cytes are neural stem cells in the adult mammalian brain [J ]. Cell : [5 ] Gage FH Coates PW Palmer TD et al. Survival and differ2 entiation of adult neuronal progenitor cells transplanted to the adult brain[j ]. Proc Natl Acad Sci USA : [6 ] Weiss S Dunne C Hewson J et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ven2 tricular neuroaxis[j ]. J Neurosci : [7 ] Tropepe V Coles BLK Chiasson BJ et al. Retinal stem cells in the adult mammalian eye[j ]. Science : [8 ] Reynolds BA Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous sys2 tem[j ]. Science : [9 ] Richards LJ Kilpatrick TJ Bartlett PF. De novo generation of neuronal cells from the adult mouse brain[j ]. Proc Natl Acad Sci USA : [10 ] John KK Hazel TG Muller T et al. Single factors direct the differentiation of stem cells from the fetal and adult central ner2 vous system[j ]. Genes Dev : [11 ] Gage FH. Mammalian neural stem cells[j ]. Science 2000

6 (3) Basic Medical Sciences and Clinics : [12 ] Bjorklund A Lindvall O. Self2repair in the brain [J ]. Sci2 ence : [13 ] Yamamoto S Nagao M Sugimori M et al. Transcription fac2 tor expression and Notch2dependent regulation of neural pro2 genitors in the adult rat spinal cord [J ]. J Neurosci : [14 ] Eriksson PS Perfilieva E Bjork2Eriksson T et al. Neuro2 genesis in the adult human hippocampus[j ]. Nat Med : [15 ] Johansson CB Svensson M Wallstedt L et al. Neural stem cells in the adult human brain[j ]. Exp Cell Research : [16 ] Vescovi AL Parati EA Gritti A et al. Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation[j ]. Exp Neurol : [17 ] Svendsen CN Borg MG Armstrong RJ E et al. A new meth2 od for the rapid and long term growth of human neural precur2 sor cells[j ]. J Neurosci Methods : [18 ] Ray J Peterson DA Schinstine M et al. Proliferation dif2 ferentiation and long2term culture of primary hippocampal neurons[j ]. Proc Natl Acad Sci USA : [19 ] McKay R. Stem cells in the central nervous system[j ]. Sci2 ence : [20 ] Ostenfeld T Cladwell MA Prowse KR et al. Human neural precursor cells express low levels of telomerase in vitro and show diminishing cell proliferation with extensive axonal out2 growth following transplantation[j ]. Exp Neurol : [21 ] Villa A Rubio FJ Navarro B et al. Human neural stem cells in vitro. A focus on their isolation and perpetuation[j ]. Biomed Pharmacother : [22 ] Caldwell MA. Recent advances in neural stem cell technolo2 gies[j ]. Trends in neuroscience : [23 ] Villa A Snyder EY Vescovi A et al. Establishment and properties of a growth factor2dependent perpetual neural stem cell line from the human CNS[J ]. Exp Neurlo : [24 ] Slinskey A Barnes D Pipas JM. Simian virus 40 large T an2 tigen J domain and Rb2binding motif are sufficient to block ap2 optosis induced by growth factor withdrawl in a neural stem cell line[j ]. J Virology : [25 ] Uchida N Buck DW He DP et al. Direct isolation of hu2 man centralnervous system stem cells[j ]. Proc Natl Acad Sci USA : [26 ] Klassen H Schwartz MR Bailey AH et al. Surface markers expressed by multipotent human and mouse neural progenitor cells include tetraspanins and non2protein epitopes[j ]. Neuro2 science Letters : [27 ] Roy NS Wang S Jiang L et al. In vitro neurogenesis by progenitor cells isolated from the sdult human hippocampus [J ]. Nat Med : [28 ] Keyoung HM Roy NS Benraiss A et al. High2yield selec2 tion and extraction of two promoter2defined phenotypes of neu2 ral stem cells from the fetal human brain[j ]. Nature Biotechn2 ology : [29 ] Mao L Lau YS Petroske E et al. Profound astrogenesis in the striatum of adult mice following nigrostriatal dopaminergic lesion by repeated MPTP administration [J ]. Brain Res Dev Brain Res : [30 ] Fallon J Reid S Kinyamu R et al. In vivo induction of massive proliferation directed migration and differentiation of neural cells in the adulet mammalian brain [ J ]. Acad Sci USA : Proc Natl [31 ] Jin K Minami M Lan JQ et al. Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal ce2 rebral ischemia in the rat [ J ]. Proc Natl Aced Sci USA : [32 ] Peterson DA. Stem cells in brain plasticity and repair [J ]. Current Opinion in Pharmacology : [33 ] Armstrong RJ E Barker RA. Neurodegeneration : a failure of neuroregeneration[j ]. Lancet : [34 ] Freed CR Greene PE Breeze RE et al. Transplantation of embryonic dopamine neurons for severe Parkinson s disease [J ]. N Engl J Med : [35 ] Ling ZD Potter ED Lipton JW et al. Differentiation of mes2 encephalic progenitor cells into dopaminergic neurons by cyto2 kines[j ]. Exp Neurol : [ 36 ] Potter ED Ling ZD Carvey PM et al. Cytokine2induced conversion of mesencephalic2derived progenitor cells into do2 pamine neurons[j ]. Cell Tissue Res : [37 ] Carvey PM Ling ZD Sortwell CE et al. A clonal line of mesencephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines : a source of cells for transplanta2 tion in Parkinson s disease[j ]. Exp Neurol : [38 ] Svendsen CN Clarke DJ Rosser AE et al. Survival and dif2 ferentiation of rat and human epidermal growth factor2respons2 ive precursor cells following grafting into the lesioned adult central nervous system[j ]. Exp Neurol : 376 -

7 218 Basic Medical Sciences and Clinics (3) 388. [39 ] Svendsen CN Caldwell MA Shen J et al. Long2term surviv2 al of human central nervous system progenitor cells transplanted into a rat model of Parkinson s disease [J ]. Exp Neurol : [40 ] Nishino H Hida H Takei N et al. Mesencephalic neural stem (progenitor) cells develop to dopaminergic neurons more strongly in dopamine2depleted striatum than in intact striatum [J ]. Exp Neurol : [41 ] Fricker J. Human neural stem cells on trial for Parkinson s disease[j ]. Mol Med Today : 144. [42 ] Toda H Takahashi J Iwakami N et al. Grafting neural stem cells improved the impaired spatial recognition in ischemic rats [J ]. Neurosci Letters : [43 ] Benedetti S Piroia B Pollo B. Gene therapy of experimental brain tumors using neural progenitor cells [J ]. Nature Medi2 cine : [44 ] Aboody KS Brown A Raioov NG et at. From the cover : neural stem cells display extensive tropism for pathology in adult brain : evidence from intracranial gliomas[j ]. Proc Natl Acad Sci USA : [45 ] Pincus DW Goodman RR Fraser RAR et al. Neural stem and progenitor cells : a strategy for gene therapy and brain re2 pair[j ]. Neurosurgery : [46 ] Kalyani AJ Rao MS. Cell lineage in the developing neural tube[j ]. Biochem Cell Biol : Progress in neural stem cells WANG Xuan WANG Kun WANG Xiao2min (Neuroscience Research Institute Peking University Beijing China) Abstract : Recently the research methods for stem cells from central nervous system and the clinical application have at2 tracted attention of CNS study. In this review the finding of neural stem cells new research techniques and therapeutic effects on the CNS disorders such as neurodegeneration diseases ischema injury and tumors by applying neural stem cells are introduced. Key words : neural stem cells ; neuroregeneration ; cell transplantation ( 211 ) The gene therapy of central nervous system disorders ZHANG Wang2ming NIU Dong2bin XU Ru2xiang et al (Neuroscience Research Institute Peking University Beijing China) Abstract : Gene therapy is a potential and new methods of treating many neurological diseases that were considered re2 fractory to current conventional treatments. By injection of viral vectors or transplantation of genetically engineered cells into specific sites of the brain the development of technologies for delivery of foreign genes into brain opened the field to promising treatments for CNS disorders. But the development of gene therapy for neurological diseases represents a more complex problem than that for other systemic disorders. Incomplete characterization of target organs ( brain and spinal cord) and additional challenges such as post2mitotic cells heterogeneity of cell types and circuits and limited access all contribute to the difficulties. For this reason this report provides an update outline of gene therapy in CNS and re2 views current researches in this filed. Key words : gene therapy ; central nervous system ; viral vectors Corresponding author : Wang Xiao2min

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