Neurological Surgery 脳神経外科34巻3号

2006年03月発行

総説

成体・成人に存在する幹細胞の分子生物学的特徴とその神経科学への応用

著者： 新郷哲郎¹ 伊達勲¹

所属機関： ¹岡山大学大学院医歯薬学総合研究科神経病態外科学

ページ範囲：P.231 - P.253

Ⅰ．は じ め に

　めざましい幹細胞研究の発展により，成体内には造血系や神経系のみならずあらゆる部位，臓器において組織幹細胞の存在が明らかにされてきた．成体脳においても脳室周囲（側脳室，第三脳室，第四脳室）や海馬に神経幹・前駆細胞が存在し，ニューロン新生（adult neurogenesis）が絶えず起こっている^112,141,182)．成体由来神経幹・前駆細胞は胎児由来とは違ったメカニズムにより維持されている．その新生ニューロンは，周辺組織（海馬，線条体，視床下部，嗅球など）に遊走（migration）し，組織の新生（renewal）および修復（repair）に関与している．機能的には，海馬では新しい記憶回路の再構築，嗅球では新しいにおいに対する嗅覚分別能や新規嗅覚の記憶に関与しているといわれている．また，神経幹・前駆細胞はニューロンだけではなく，アストロサイトやオリゴデンドロサイトを周辺組織に供給し，損傷した組織，特に軸索損傷の修復などに関与している．最近の研究により，神経幹細胞（neural stem cell，NSC）はアストロサイトのマーカーであるGFAPを発現していることが発見された⁴³⁾．損傷が起こった脳周辺に集積するアストロサイトの中に神経幹・前駆細胞細胞が存在する可能性がある．このような機能を持った神経幹・前駆細胞細胞を細胞移植というかたちで用いる治療や，内因性の幹細胞を利用した治療を目標として，さかんに研究が行われている．

　全能性を有する胚性幹細胞（embryonic stem cell, ES細胞）に関しては，中枢神経系を構成する細胞に分化誘導する方法が開発され，最近ではクローン技術を用いたクローンES細胞を用いた研究も行われ¹²⁾，この細胞を用いた移植研究が進んでいる．特に，ES細胞をドパミンニューロンへ分化誘導させる方法が数多く開発され，基礎実験ではすばらしい成果があがっているので，パーキンソン病の患者治療のための臨床応用も近いと思われる．また，骨髄由来間質幹細胞（mesenchymal stem cell, MSC）の中にES細胞と同様の能力を持った細胞が存在し神経細胞に分化することも可能であり^65,140)，また，末梢血の中にもこの細胞が循環している（成人多能性幹細胞，multipotent adult progenitor cells, MAPCs）⁷⁴⁾．これらの細胞は，自家移植が可能であることから移植治療において注目され，臨床応用も試みられている．

　本稿では，成体・成人に存在する幹細胞（神経幹細胞と間質幹細胞）の分子生物学的特徴と，これらを用いた再生治療についてまとめる．また，幹細胞の概念に基づいた脳腫瘍幹細胞（brain tumor stem cell）の存在が注目されているが，それに関する最近の知見について述べる．

参考文献

1）Aberg MA, Aberg ND, Hedbacker H, et al：Peripheral infusion of IGF-I selectively induces neurogenesis in the adult rat hippocampus. J Neurosci 20：2896-2903, 2000

2）Ahmed S, Reynolds BA, Weiss S：BDNF enhances the differentiation but not the survival of CNS stem cell-derived neuronal precursors. J Neurosci 15：5765-5778, 1995

3）Ajo R, Cacicedo L, Navarro C, et al：Growth hormone action on proliferation and differentiation of cerebral cortical cells from fetal rat. Endocrinology 144：1086-1097, 2003

4）Akerud P, Canals JM, Snyder EY, et al：Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson’s disease. J Neurosci 21：8108-8118, 2001

5）Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, et al：Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425：968-973, 2003

6）Arsenijevic Y, Villemure JG, Brunet JF, et al：Isolation of multipotent neural precursors residing in the cortex of the adult human brain. Exp Neurol 170：48-62, 2001

7）Arsenijevic Y, Weiss S, Schneider B, et al：Insulin-like growth factor-I is necessary for neural stem cell proliferation and demonstrates distinct actions of epidermal growth factor and fibroblast growth factor-2. J Neurosci 21：7194-7202, 2001

8）Arvidsson A, Collin T, Kirik D, et al：Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 8：963-970, 2002

9）Baker SA, Baker KA, Hagg T：Dopaminergic nigrostriatal projections regulate neural precursor proliferation in the adult mouse subventricular zone. Eur J Neurosci. 20：575-579, 2004

10）Baker SA, Baker KA, Hagg T：D3 dopamine receptors do not regulate neurogenesis in the subventricular zone of adult mice. Neurobiol Dis 18：523-527, 2005

11）Banasr M, Hery M, Printemps R, et al：Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology. 29：450-460, 2004

12）Barberi T, Klivenyi P, Calingasan NY, et al：Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat Biotechnol. 21：1200-1207, 2003

13）Bang OY, Lee JS, Lee PH, et al：Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 57：874-882, 2005

14）Bartlett PF, Brooker GJ, Faux CH, et al：Regulation of neural stem cell differentiation in the forebrain. Immunol Cell Biol. 76：414-418, 1998

15）Bonnet D, Dick JE：Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Med. 3：730-737, 1997

16）Brandt MD, Jessberger S, Steiner B, et al：Transient calretinin expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice. Mol Cell Neurosci. 24：603-613, 2003

17）Brannvall K, Bogdanovic N, Korhonen L, et al：19-Nortestosterone influences neural stem cell proliferation and neurogenesis in the rat brain. Eur J Neurosci 21：871-878, 2005

18）Brazelton TR, Rossi FM, Keshet GI, et al：From marrow to brain：expression of neuronal phenotypes in adult mice. Science 290：1775-1779, 2000

19）Bull ND, Bartlett PF：The adult mouse hippocampal progenitor is neurogenic but not a stem cell. J Neurosci 25：10815-10821, 2005

20）Butovsky O, Ziv Y, Schwartz A, et al：Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31：149-160, 2006

21）Cai J, Wu Y, Mirua T, et al：Properties of a fetal multipotent neural stem cell (NEP cell). Dev. Biol 251：221-240, 2002

22）Cai J, Cheng A, Luo Y, et al：Membrane properties of rat embryonic multipotent neural stem cells. J Neurochem 88：212-226, 2004

23）Cameron HA, McKay RD：Restoring production of hippocampal neurons in old age. Nat Neurosci 2：894-897, 1999

24）Cameron HA, Woolley CS, Gould E：Adrenal steroid receptor immunoreactivity in cells born in the adult rat dentate gyrus. Brain Res 611：342-346, 1993

25）Campbell K, Göts M：Radial glia：multi-purpose cells for vertebrate brain development. Trends Neurosci 25：235-238, 2002

26）Cao L, Jiao X, Zuzga DS, et al：VEGF links hippocampal activity with neurogenesis, learning and memory. Nat Genet 36：827-835, 2004

27）Capela A, Temple S：LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal, Neuron 35：865-875, 2002

28）Catena R, Tiveron C, Ronchi A, et al：Conserved POU binding DNA sites in the Sox2 upstream enhancer regulate gene expression in embryonic and neural stem cells. J Biol Chem 279：41846-41857, 2004

29）Chen JH, Wen L, Dupuis S, et al：The N-terminal leucine-rich regions in Slit are sufficient to repel olfactory bulb axons and subventricular zone neurons. J Neurosci 21：1548-1556, 2001

30）Chen J, Li Y, Wang Z, et al：Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32：1005-1011, 2003

31）Cheng Y, Black IB, DiCicco-Bloom E：Hippocampal granule neuron production and population size are regulated by levels of bFGF. Eur J Neurosci 15：3-12, 2002

32）Chirumamilla S, Sun D, Bullock MR, et al：Traumatic brain injury induced cell proliferation in the adult mammalian central nervous system. J Neurotrauma 19：693-703, 2002

33）Chlasson BJ, Tropepe V, Morshead CM, et al：Adult mammalian forebrain ependymal and subependymal cells demonstrate proliferative potential, but only subependymal cells have neural stem cell characteristics. J Neurosci 19：4462-4472, 1999

34）Chojnacki A, Weiss S：Isolation of a novel platelet-derived growth factor-responsive precursor from the embryonic ventral forebrain. J Neurosci 24：10888-10899, 2004

35）Chojnacki A, Shimazaki T, Gregg C, et al：Glycoprotein 130 signaling regulates Notch1 expression and activation in the self-renewal of mammalian forebrain neural stem cells. J Neurosci 23：1730-1741, 2003

36）Corotto FS, Henegar JR, Maruniak JA：Odor deprivation leads to reduced neurogenesis and reduced neuronal survival in the olfactory bulb of the adult mouse. Neuroscience 61：739-744, 1994

37）Curtis MA, Penney EB, Pearson AG, et al：Increased cell proliferation and neurogenesis in the adult human Huntington’s disease brain. Proc Natl Acad Sci U S A 100：9023-9027, 2003

38）Dash PK, Mach SA, Moore AN：Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury. J Neurosci Res 63：313-319, 2001

39）Desouza LA, Ladiwala U, Daniel SM, et al：Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain. Mol Cell Neurosci 29：414-426, 2005

40）Dezawa M, Ishikawa H, Itokazu Y, et al：Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science 309：314-317, 2005

41）Dezawa M, Kanno H, Hoshino M, et al：Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 113：1701-1710, 2004

42）Digicaylioglu M, Lipton SA：Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412：641-647, 2001

43）Doetsch F, Caille I, Lim DA, et al：Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97：703-716, 1999

44）Doetsch F：A niche for adult neural stem cells. Curr Opin Genet Dev 13：543-550, 2003

45）Doetsch F, Garcia-Verdugo JM, Alvarez-Buylla A：Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain J Neurosci 17：5046-5061, 1997

46）Doetsch F, Petreanu L, Caille I, et al：EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36：1021-1034, 2002

47）Dziewczapolski G, Lie DC, Ray J, et al：Survival and differentiation of adult rat-derived neural progenitor cells transplanted to the striatum of hemiparkinsonian rats. Exp Neurol 183：653-664, 2003

48）Ehrenreich H, Hasselblatt M, Dembowski C, et al：Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8：495-505, 2002

49）Emsley JG, Hagg T：Endogenous and exogenous ciliary neurotrophic factor enhances forebrain neurogenesis in adult mice. Exp Neurol 183：298-310, 2003

50）Emsley JG, Hagg T：alpha6beta1 integrin directs migration of neuronal precursors in adult mouse forebrain. Exp Neurol 183：273-285, 2003

51）Galli R, Binda E, Orfanelli U, et al：Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma. Cancer Res 64：7011-7021, 2004

52）Gates MA, Thomas LB, Howard EM, et al：Cell and molecular analysis of the developing and adult mouse subventricular zone of the cerebral hemispheres. J Comp Neurol 361：249-266, 1995

53）Giachino C, Galbiati M, Fasolo A, et al：Effects of progesterone derivatives, dihydroprogesterone and tetrahydroprogesterone, on the subependymal layer of the adult rat. J Neurobiol 58：493-502, 2004

54）Gould E, Beylin A, Tanapat P, et al：Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2：260-265, 1999

55）Gould E, Tanapat P, McEwen BS, et al：Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci U S A 95：3168-3171, 1998

56）Hack I, Bancila M, Loulier K, et al：Reelin is a detachment signal in tangential chain-migration during postnatal neurogenesis. Nat Neurosci 5：939-945, 2002

57）Hagan M, Wennersten A, Meijer X, et al：Neuroprotection by human neural progenitor cells after experimental contusion in rats. Neurosci Lett 351：149-152, 2003

58）Harrist A, Beech RD, King SL, et al：Alteration of hippocampal cell proliferation in mice lacking the beta 2 subunit of the neuronal nicotinic acetylcholine receptor. Synapse 54：200-206, 2004

59）Hattiangady B, Rao MS, Shetty AK：Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis 17：473-490, 2004

60）Hemmati HD, Nakano I, Lazareff JA, et al：Cancerous stem cell can arise from pediatric brain tumors. PNAS 100：15178-15183, 2003

61）Herzog EL, Chai L, Krause DS：Plastisity of marrow-derived stem cells. Blood 102：3483-3493, 2003

62）Hienola A, Pekkanen M, Raulo E, et al：HB-GAM inhibits proliferation and enhances differentiation of neural stem cells. Mol Cell Neurosci 26：75-88, 2004

63）Hofstetter CP, Holmstrom NAV, Lilja JA, et al：Allodynia limits the usefulness of intraspinal neural stem cell grafts；directed differentiation improves outcome. Nat Neurosci 8：346-353, 2005

64）Hoglinger GU, Rizk P, Muriel MP, et al：Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci 7：726-735, 2004

65）Herzog EL, Chai L, Krause DS：Plastisity of marrow-derived stem cells. Blood 102：3483-3493, 2003

66）Hsieh J, Aimone JB, Kaspar BK, et al：IGF-I instructs multipotent adult neural progenitor cells to become oligodendrocytes. J Cell Biol 164：111-122, 2004

67）Hsieh J, Nakashima K, Kuwabara T, et al：Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci U S A 101：16659-16664, 2004

68）Hutchins JB, Casagrande VA：Vimentin：changes in distribution during brain development. Glia 2：55-66, 1989

69）Ignatova TN, Kukekov VG, Laywell ED, et al：Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39：193-206, 2002

70）Imitola J, Raddassi K, Park KI, et al：Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A 101：18117-18122, 2004

71）Iwanami A, Kaneko S, Nakamura M, et al：Transplantation of human neural stem cells for spinal cord injury in primates. J Neurosci Res 80：182-190, 2005

72）Jackson-Guilford J, Leander JD, Nisenbaum LK：The effect of streptozotocin-induced diabetes on cell proliferation in the rat dentate gyrus. Neurosci Lett 293：91-94, 2000

73）Jacques TS, Relvas JB, Nishimura S, et al：Neural precursor cell chain migration and division are regulated through different beta1 integrins. Development 125：3167-3177, 1998

74）Jiang Y, Henderson D, Blackstad M, et al：Neuroectodermal differentiation from mouse multipotent adult progenitor cells. Proc Natl Acad Sci U S A 100 Suppl 1：11854-11860, 2003

75）Jin K, Galvan V, Xie L, et al：Enhanced neurogenesis in Alzheimer’s disease transgenic (PDGF-APPSw,Ind) mice. Proc Natl Acad Sci U S A 101：13363-13367, 2004

76）Jin K, Minami M, Lan JQ, et al：Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci U S A 98：4710-4715, 2001

77）Jin K, Peel AL, Mao XO, et al：Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci U S A 101：343-347, 2004

78）Jin K, Zhu Y, Sun Y, et al：Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A 99：11946-11950, 2002

79）Johansson CB, Momma S, Clarke DL, et al：Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96：25-34, 1999

80）Johe KK, Hazel TG, Muller T, et al：Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev 10：3129-3140, 1996

81）Kempermann G, Jessberger S, Steiner B, et al：Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27：447-452, 2004

82）Kempermann G, Kuhn HG, Gage FH：More hippocampal neurons in adult mice living in an enriched environment. Nature 386：493-495, 1997

83）Keyoung HM, Roy NS, Benraiss A, et al：High-yield selection and extraction of two promoter-defined phenotypes of neural stem cells from the fetal human brain. Nat Biotechnol 19：843-850, 2001

84）Kim M, Morshead CM：Distinct populations of forebrain neural stem and progenitor cells can be isolated using side-population analysis. J Neurosci 23：10703-10709, 2003

85）Kippin TE, Kapur S, van der Kooy D：Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. J Neurosci 25：5815-5823, 2005

86）Klein RS, Rubin JB, Gibson HD, et al：SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development 128：1971-1981, 2001

87）Kondo T, Setoguchi T, Taga T：Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. PNAS 101：781-786, 2004

88）Kopen GC, Prockop DJ, Phinney DG：Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate ioto astrocytes after injection into neonatal mouse brain. Proc Natl Acad Sci U S A 96：10771-10716, 1999

89）Kuhn HG, Dickinson-Anson H, Gage FH：Neurogenesis in the dentate gyrus of the adult rat：age-related decrease of neuronal progenitor proliferation. J Neurosci 16：2027-2033, 1996

90）Kulkarni VA, Jha S, Vaidya VA：Depletion of norepinephrine decreases the proliferation, but does not influence the survival and differentiation, of granule cell progenitors in the adult rat hippocampus. Eur J Neurosci 16：2008-2012, 2002

91）Kurozumi K, Nakamura K, Tamiya T, et al：BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol Ther 9：189-197, 2004

92）Lai K, Kaspar BK, Gage FH, et al：Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci 6：21-27, 2003

93）Laywell ED, Raki P, Kukelov VG, et al：Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci USA 97：13883-13888, 2000

94）Lee J, Duan W, Long JM, et al：Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats. J Mol Neurosci. 15：99-108, 2000

95）Lemaire V, Aurousseau C, Le Moal M, et al：Behavioural trait of reactivity to novelty is related to hippocampal neurogenesis. Eur J Neurosci 11：4006-4014, 1999

96）Lendahl U, Zimmerman LB, McKay RD：CNS stem cells express a new class of intermediate filament protein. Cell 60：585-95, 1990

97）Leone DP, Relvas JB, Campos LS, et al：Regulation of neural progenitor proliferation and survival by beta1 integrins. J Cell Sci 118：2589-2599, 2005

98）Lim DA, Tramontin AD, Trevejo JM, et al：Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28：713-726, 2000

99）Limke TL, Cai J, Miura T, et al：Distinguishing features of progenitor cells in the late embryonic and adult hippocampus. Dev Neurosci 25：257-272, 2003

100）Liu J, Solway K, Messing RO, et al：Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18：7768-7778, 1998

101）Llado J, Haenggeli C, Maragakis NJ, et al：Neural stem cells protect against glutamate-induced excitotoxicity and promote survival of injured motor neurons through the secretion of neurotrophic factors. Mol Cell Neurosci 27：322-331, 2004

102）Lois C, Alvarez-Buylla A：Long-distance neuronal migration in the adult mammalian brain. Science 264：1145-1148, 1994

103）Lois C, Garcia-Verdugo JM, Alvarez-Buylla A：Chain migration of neuronal precursors. Science 271：978-981, 1996

104）Louissaint A Jr, Rao S, Leventhal C, et al：Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34：945-960, 2001

105）Lu M, Grove EA, Miller RJ：Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc Natl Acad Sci U S A 99：7090-7095, 2002

106）Lu L, Bao G, Chen H, et al：Modification of hippocampal neurogenesis and neuroplasticity by social environments. Exp Neurol 183：600-9, 2003

107）Luskin MB：Restricted proliferation and migration of postnatally generated neurons derived from the forebrain subventricular zone. Neuron 11：173-189, 1993

108）Magavi SS, Leavitt BR, Macklis JD：Induction of neurogenesis in the neocortex of adult mice. Nature 405：951-955, 2000

109）Malberg JE, Duman RS：Cell proliferation in adult hippocampus is decreased by inescapable stress：reversal by fluoxetine treatment. Neuropsychopharmacology 28：1562-1571, 2003

110）Maric D, Maric I, Chang YH, et al：Prospective cell sorting of embryonic rat neural stem cells and neuronal and glial progenitors reveals selective effects of basic fibroblast growth factor and epidermal growth factor on self-renewal and differentiation. J Neurosci 23：240-251, 2003

111）Mercier F, Kitasako JT, Hatton GI：Anatomy of the brain neurogenic zones revisited：fractones and the fibroblast/macrophage network. J Comp Neurol 451：170-188, 2002

112）Ming GL, Song H：Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28：223-250, 2005

113）Mohapel P, Leanza G, Kokaia M, et al：Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning. Neurobiol Aging 26：939-946, 2005

114）Moon C, Yoo JY, Matarazzo V, et al：Leukemia inhibitory factor inhibits neuronal terminal differentiation through STAT3 activation. Proc Natl Acad Sci U S A 99：9015-9020, 2002

115）Morshead CM, Benveniste P, lacove NN, et al：Hematopoietic competence is a rare property of neural stem cells and may depend on genetic and epigenetic alterations. Nat Med 8：268-273, 2002

116）Morshead CM, Reynolds BA, Craig CG, et al：Neural stem cells in the adult mammalian forebrain：a relatively quiescent subpopulation of subependymal cells. Neuron 13：1071-1082, 1994

117）Munoz JR, Stoutenger BR, Robinson AP, et al：Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc Natl Acad Sci U S A 102：18171-18176, 2005

118）Muraoka K, Shingo T, Yasuhara T, et al：The high integration potential of autologous neural stem cell transplantation compared with allogeneic transplantation in adult rat hippocampus. Exp Neurol (in press), 2006

119）Nacher J, Rosell DR, Alonso-Llosa G, et al：NMDA receptor antagonist treatment induces a long-lasting increase in the number of proliferating cells, PSA-NCAM-immunoreactive granule neurons and radial glia in the adult rat dentate gyrus. Eur J Neurosci 13：512-520, 2001

120）Nakatomi H, Kuriu T, Okabe S, et al：Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110：429-441, 2002

121）Ng KL, Li JD, Cheng MY, et al：Dependence of olfactory bulb neurogenesis on prokineticin 2 signaling. Science 308：1923-1927, 2005

122）Nguyen-Ba-Charvet KT, Picard-Riera N, Tessier-Lavigne M, et al：Multiple roles for slits in the control of cell migration in the rostral migratory stream. J Neurosci 24：1497-1506, 2004

123）Nixon K, Crews FT：Temporally specific burst in cell proliferation increases hippocampal neurogenesis in protracted abstinence from alcohol. J Neurosci 24：9714-9722, 2004

124）Nomura T, Honmou O, Harada K, et al：I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience 136：161-169, 2005

125）Nunes MC, Roy NS, Keyoung HM, et al：Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med. 9：439-447, 2003

126）Ormerod BK, Lee TT, Galea LA：Estradiol enhances neurogenesis in the dentate gyri of adult male meadow voles by increasing the survival of young granule neurons. Neuroscience 128：645-654, 2004

127）Pagano SF, Impagnatiello F, Girelli M, et al：Isolation and characterization of neural stem cells from the adult human olfactory bulb. Stem Cells 18：295-300, 2000

128）Palmer TD, Schwartz PH, Taupin P, et al：Cell culture. Progenitor cells from human brain after death. Nature 411：42-43, 2001

129）Palmer TD, Willhoite AR, Gage FH：Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425：479-494, 2000

130）Palmer TD, Markakis EA, Willhoite AR, et al：Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci 19：8487-8497, 1997

131）Parent JM, Valentin VV, Lowenstein DH：Prolonged seizures increase proliferating neuroblasts in the adult rat subventricular zone-olfactory bulb pathway. J Neurosci 22：3174-3188, 2002

132）Pencea V, Bingaman KD, Wiegand SJ, et al：Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci 21：6706-6717, 2001

133）Peretto P, Giachino C, Aimar P, et al：Chain formation and glial tube assembly in the shift from neonatal to adult subventricular zone of the rodent forebrain. J Comp Neurol 487：407-427, 2005

134）Pluchino S, Quattrini A, Brambilla E, et al：Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422：688-694, 2003

135）Pluchino S, Zanotti L, Rossi B, et al：Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436：266-271, 2005

136）Potten CS, Booth C, Tudor GL, et al：Identification of a putative intestinal stem cell and early lineage marker; musashi-1. Differentiation 71：28-41, 2003

137）Pevny LH, Sockanathan S, Placzek M, et al：A role for SOX1 in neural determination. Development 125：1967-1978, 1998

138）Quinones-Hinojosa A, Sanai N, Soriano-Navarro M, et al：Cellular composition and cytoarchitecture of the adult human subventricular zone：A niche of neural stem cells. J Comp Neurol 494：415-434, 2006

139）Rasika S, Nottebohm F, Alvarez-Buylla A：Testosterone increases the recruitment and/or survival of new high vocal center neurons in adult female canaries. Proc Natl Acad Sci U S A 91：7854-7858, 1994

140）Reh TA：Neural stem cells：form and function. Nat Neurosci 5：392-294, 2002

141）Reynolds BA, Weiss S：Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255：1707-1710, 1992

142）Reynolds BA, Tetzlaff W, Weiss S：A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12：4565-4574, 1992

143）Reynolds BA, Weiss S：Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 175：1-13, 1996

144）Rietze RL, Valcanis H, Brooker GF, et al：Purification of a pluripotent neural stem cell from the adult mouse brain. Nature 412：736-739, 2001

145）Rochefort C, Gheusi G, Vincent JD, et al：Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J Neurosci 22：2679-2689, 2002

146）Roy NS, Wang S, Jiang L, et al：In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med 6：271-277, 2000

147）Roy NS, Benraiss A, Wang S, et al：Promoter-targeted selection and isolation of neural progenitor cells from the adult human ventricular zone. J Neurosci Res. 59：321-331, 2000

148）Ruscher K, Freyer D, Karsch M, et al：Erythropoietin is a paracrine mediator of ischemic tolerance in the brain：evidence from an in vitro model. J Neurosci 22：10291-10301, 2002

149）Saghatelyan A, de Chevigny A, Schachner M, et al：Tenascin-R mediates activity-dependent recruitment of neuroblasts in the adult mouse forebrain. Nat Neurosci 7：347-356, 2004

150）Sakakibara S, Imai T, Hamaguchi K, et al：Mouse-Musashi-1, a neural RNA-binding protein highly enriched in the mammalian CNS stem cell. Dev Biol 176：230-242, 1996

151）Sanai N, Tramontin AD, Quinones-Hinojosa A, et al：Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427：740-744, 2004

152）Santarelli L, Saxe M, Gross C, et al：Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301：805-859, 2003

153）Seaberg RM, van der Kooy D：Adult rodent neurogenic regions：the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J Neurosci 22：1784-1793, 2002

154）Seki T, Arai Y：Age-related production of new granule cells in the adult dentate gyrus. Neuroreport 6：2479-2482, 1995

155）Seri B, Garcia-Verdugo JM, McEwen BS, et al：Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci 21：7153-7160, 2001

156）Shen Q, Goderie SK, Jin L, et al：Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304：1338-1340, 2004

157）Shi Y, Chichung Lie D, Taupin P, et al：Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature 427：78-83, 2004

158）Shimazaki T, Shingo T, Weiss S：The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells. J Neurosci 21：7642-7653, 2001

159）Shingo T, Sorokan ST, Shimazaki T, et al：Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci 21：9733-9743, 2001

160）Shingo T, Gregg C, Enwere E, et al：Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 299：117-120, 2003

161）Shingo T, Enwere E, Gregg C, et al：Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci 24：8354-8365, 2004

162）新郷哲郎，村岡賢一郎，高橋和也，他：神経疾患に対する成体由来神経幹細胞移植：自家細胞移植をめざして．再生医療 3：33-38, 2004

163）Singh SK, Clarke ID, Terasaka M, et al：Identification of a cancer stem cell in human brain tumors. Cancer Res. 63：5821-5828, 2003

164）Singh SK, Hawkins C, Clarke ID, et al：Identification of human brain tumour initiating cells. Nature 432：396-401, 2004

165）Song H, Stevens CF, Gage FH：Astroglia induce neurogenesis from adult neural stem cells. Nature. 417：39-44, 2002

166）Storms RW, Trujillo AP, Springer JB, et al：Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity. Proc Natl Acad Sci U S A 96：9118-9123, 1999

167）Stumm RK, Rummel J, Junker V, et al：A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain：isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J Neurosci. 22：5865-5878, 2002

168）Sun W, Winseck A, Vinsant S, et al：Programmed cell death of adult-generated hippocampal neurons is mediated by the proapoptotic gene Bax. J Neurosci 24：11205-11213, 2004

169）Taga T, Fukuda S：Role of IL-6 in the neural stem cell differentiation. Clin Rev Allergy Immunol 28：249-256, 2005

170）Tanapat P, Hastings NB, Rydel TA, et al：Exposure to fox odor inhibits cell proliferation in the hippocampus of adult rats via an adrenal hormone-dependent mechanism. J Comp Neurol 437：496-504, 2001

171）Tanapat P, Hastings NB, Reeves AJ, et al：Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci 19：5792-5801, 1999

172）Terada N, Hamazaki T, Oka M, et al：Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature. 416：542-545, 2002

173）Tropepe V, Craig CG, Morshead CM, et al：Transforming growth factor-alpha null and senescent mice show decreased neural progenitor cell proliferation in the forebrain subependyma. J Neurosci 17：7850-7859, 1997

174）Tsai RY, McKay RD：A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev 16：2991-3003, 2002

175）Uchida N, Buck DW, He D, et al：Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci U S A 97：14720-14725, 2000

176）van Praag H, Kempermann G, Gage FH：Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci 2：266-270, 1999

177）Verfaillie CM：Multipotent adult progenitor cells：an update. Novartis Found Symp 265：55-61, 2005

178）Vescovi AL, Reynolds BA, Fraser DD, et al：bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells. Neuron 31：951-966, 1993

179）Vroemen M, Aigner L, Winkler J, et al：Adult neural progenitor cell grafts survive after acute spinal cord injury and integrate along axonal pathways. Eur J Neurosci. 18：743-751, 2003

180）Weimann JM, Johansson CB, Trejo A, et al：Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nat Cell Biol 5：959-966, 2003

181）Weimann JM, Charlton CA, Brazelton TR, et al：Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci U S A 100：2088-2093, 2003

182）Weiss S, Dunne C, Hewson J, et al：Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci 16：7599-7609, 1996

183）White JK, Auerbach W, Duyao MP, et al：Huntingtin is required for neurogenesis and is not impaired by the Huntington’s disease CAG expansion. Nat Genet 17：404-410, 1997

184）Widera D, Holtkamp W, Entschladen F, et al：MCP-1 induces migration of adult neural stem cells. Eur J Cell Biol 83：381-387, 2004

185）Winner B, Geyer M, Couillard-Despres S, et al：Striatal deafferentation increases dopaminergic neurogenesis in the adult olfactory bulb. Exp Neurol 197：113-121, 2006

186）Xiao M, Klueber KM, Lu C, et al：Human adult olfactory neural progenitors rescue axotomized rodent rubrospinal neurons and promote functional recovery. Exp Neurol 194：12-30, 2005

187）Yuan X, Curtin J, Xiong Y, et al：Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 23：9392-9400, 2004

188）Zheng W, Nowakowski RS, Vaccarino FM：Fibroblast growth factor 2 is required for maintaining the neural stem cell pool in the mouse brain subventricular zone. Dev Neurosci 26：181-196, 2004