Abstract
The study of the basic physiology of the neural precursors generated during brain development is driven by two inextricably linked goals. First, such knowledge is instrumental to our understanding of how the high degree of cellular complexity of the mature central nervous system (CNS) is generated, and how to dissect the steps of proliferation, fate commitment, and differentiation that lead early pluripotent neural progenitors to give rise to mature CNS cells. Second, it is hoped that the isolation, propagation, and manipulation of brain precursors and, particularly, of multipotent neural stem cells (NSCs), will lead to therapeutic applications in neurological disorders. The debate is still open concerning the most appropriate definition of a stem cell and on how it is best identified, characterized, and manipulated. By adopting an operational definition of NSCs, we review some of the basic findings in this area and elaborate on their potential threapeutic applications. Further, we discuss recent evidence from our two groups that describe, based on that rigorous definition, the isolation and propagation of clones of NSCs from the human fetal brain and illustrate how they have begun to show promise for neural cell replacement and molecular support therapy in models of degenerative CNS diseases. The extensive propagation and engraftment potential of human CNS stem cells may, in the not‐too‐distant future, be directed towards genuine clinical therapeutic ends, and may open novel and multifaceted strategies for redressing a variety of heretofore untreatable CNS dysfunctions.
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References
- 1. Alvarez‐Buylla A, Temple S (eds.) (1998) Stem Cells, J Neurobiol 36:105–314. [PubMed] [Google Scholar]
- 2. Anderson DK, Howland DR, Reier PJ. (1995) Foetal neural grafts and repair of the injured spinal cord. Brain Pathol 5:451–57. [DOI] [PubMed] [Google Scholar]
- 3. Anton R, Kordower JH, Maidment NT, (1994) Neural‐targeted gene therapy for rodent and primate hemiparkinsonism. Exp Neurol 127:207–18. [DOI] [PubMed] [Google Scholar]
- 4. Auguste KI, Nakajima K, Miyata T, Ogawa M, Mioshiba K, Snyder EY. (1996) Neural progenitor transplantation into newborn reeler cerebellum may rescue certain aspects of mutant cytoarchitecture. Soc Neurosci Abstr 22:484. [Google Scholar]
- 5. Bartlett PF, Reid HH, Bailey KA, Bernard O. (1988) Immortalization of mouse neural precursor cells by the c‐myc oncogene. Proc Natl Acad Sci USA 85:3255–3259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Bjorklund A. (1993) Better cells for brain repair. Nature 362:414–415. [DOI] [PubMed] [Google Scholar]
- 7. Blakemore WF, Olby NJ, Franklin RJM. (1995) The use of transplanted glial cells to reconstruct glial environments in the CNS. Brain Pathol 5:443–450. [DOI] [PubMed] [Google Scholar]
- 8. Brüstle O, Choudhary K, Karram K, Hattner A, Murray K, Dubois‐Dalcq M, McKay R. (1998) Chimeric brains generated by intarventricular transplantation of fetal human brain cells into embryonic rats. Nat Biotec 11 (16):1040–1049. [DOI] [PubMed] [Google Scholar]
- 9. Brüstle O., McKay R. (1996) Neuronal progenitors as a tool for cell replacement in the CNS. Curr Opin Neurobiol 6:688–695. [DOI] [PubMed] [Google Scholar]
- 10. Cameron HA, McKay R. (1998) Stem cells and neurogenesis in the adult brain. Curr Opin Neurobiol 8 (1):677–680. [DOI] [PubMed] [Google Scholar]
- 11. Carpenter MK, Winkler C, Fricker R, Wong SC, Greco C, Emerich D, Chen E‐Y, Chu Y, Kordower J, Messing A, Bjorklund A, Hammang JP. (1996) Transplantation of EGF‐responsive neural stem cells derived from GFAP‐hNGF transgenic mice attenuates excitotoxic striatal lesions. Soc Neurosci Abstr 22:232.4. [Google Scholar]
- 12. Cattaneo E, Magrassi L, Santi L, Butti G, McKay RDG, Pezzota S. (1993) Transplanting embryonic striatal cell lines into the embryonic rat brain. Soc Neurosci Abstr 19:107.6. [Google Scholar]
- 13. Cattaneo E, Magrassi L, Butti G, Santi L, Giavazzi A, Pezzotta S. (1994) A short term analyses of the behavior of conditionally immortalized neuronal progenitors and primary neuroepithelial cells implanted into the fetal rat brain. Dev Brain Res 83:197–208. [DOI] [PubMed] [Google Scholar]
- 14. Chalmers‐Redman RME, Priestley T, Kemp JA, Fine A. (1997) In vitro propagation and inducible differentiation of multipotential progenitor cells from human foetal brain. Neurosci 76:1211–1128. [DOI] [PubMed] [Google Scholar]
- 15. Ciccolini F, Svendsen CN. (1998) Fibroblast Growth Factor 2 (FGF‐2) promotes acquisition of Epidermal Growth Factor (EGF) responsiveness in mouse striatal precursor cells: identification of neural precursors responding to both EGF and FGF‐2. J Neurosci 18:7869–7880. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Coats S, Flanagan WM, Nourse J, Roberts JM. (1996) Requirement of p‐27kip 1 for restriction point control of the fibroblast cell cycle. Science 272:877–880. [DOI] [PubMed] [Google Scholar]
- 17. Craig CG, Tropepe V, Morshead CM, Reynolds BA, Weiss S, van der Kooy D. (1996) In vivo growth factor expansion of endogenous subependymal neural precursor cell populations in the adult mouse brain. J Neurosci 16:2694–2658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Daadi M, Arcellana‐Panlilio MY, Weiss S. (1998) Activin co‐operates with fibroblast growth factor 2 to regulate tyrosine hydroxylase expression in the basal forebrain ventricular zone progenitors. Neurosci 86 (3):867–80. [DOI] [PubMed] [Google Scholar]
- 19. Davis AA, Temple S. (1994) A self‐renewing multipotential stem cell in embryonic rat cerebral cortex. Nature 372:263–266. [DOI] [PubMed] [Google Scholar]
- 20. Deacon T, Schumacher J, Dinsmore J, Thomas C, Palmer P, Kott S, Edge A, Penney D, Kassissieh S, Dempsey P, Isacson O. (1997) Histological evidence of foetal pig neural cell survival after transplantation into a patient with Parkinson's disease. Nat Med 3:350–353. [DOI] [PubMed] [Google Scholar]
- 21. Doetsch F, Garcia‐Verdugo JM, Alvarez‐Buylla A. (1997) Cellular composition and three‐dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci 17:5046–5061. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Duncan ID. (1996) Glial cell transplantation and remyelination of the central nervous system. Neuropath Appl Neurobiol 22:87–100. [DOI] [PubMed] [Google Scholar]
- 23. Eisenman RN, Cooper JA. (1995) Signal transduction: beating a path to Myc. Nature 378:438–439. [DOI] [PubMed] [Google Scholar]
- 24. Eriksonn PS, Perfilieva E, Birok‐Erikson T, Alborn AM, Nordborg C, Peterson D, Gage FH. (1998) Neurogenesis in the adult human hippocampus. Nat Med 4 (11):1313–1317. [DOI] [PubMed] [Google Scholar]
- 25. Fisher LJ, Gage FH. (1993) Grafting in the mammalian central nervous system. Physiol Rev 73:583–616. [DOI] [PubMed] [Google Scholar]
- 26. Fisher LJ. (1997) Neural precursor cells: application for the study and repair of the central nervous system. Neurobiol Dis 4:1–22. [DOI] [PubMed] [Google Scholar]
- 27. Flax JD, Snyder EY. (1995) Transplantation of CNS stem‐cells like as a possible therapy in a mouse model of spinal cord dysfunction. Soc Neurosci Abstr 21:2028. [Google Scholar]
- 28. Flax JD, Aurora S. Yang C, Simonin C, Wills AM, Billinghurst LL, Sidman RL, Wolfe JH, Kim SU, Snyder EY. (1998) Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat Biotec 11 (16):1033–1039. [DOI] [PubMed] [Google Scholar]
- 29. Frederiksen K, Jat PS, Valtz N, Levy D, McKay R (1988) Immortalization of precursor cells from the mammalian CNS. Neuron 1:439–448. [DOI] [PubMed] [Google Scholar]
- 30. Frim DM, Uhler TA, Short MP, Ezzedine ZD, Klagsbrun M, Breakefield XO, Isacson O. (1993a) Effects of biologically delivered NGF, BDNF and bFGF on striatal excitotoxic lesions. Neuroreport 4:367–370. [DOI] [PubMed] [Google Scholar]
- 31. Gage FH, Coates PW, Palmer TD (1995) Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci USA 92:11879–11883. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Gage FH, Ray J, Fisher LJ. (1995) Isolation, characterization and use of stem cells from the CNS. Ann Rev Neurosci 18:159–162. [DOI] [PubMed] [Google Scholar]
- 33. Gage FH. (1998) Cell therapy. Nature suppl. 392 (6679): 18–24. [PubMed] [Google Scholar]
- 34. Gage FH. (1998) Stem cells of the central nervous system. Curr Opin Neurobiol 8 (5):671–676. [DOI] [PubMed] [Google Scholar]
- 35. Galaktionov K, Chen C, Beach D. (1996) Cdc25 cell‐cycle phosphatase as a target of c‐myc. Nature 382:511–517. [DOI] [PubMed] [Google Scholar]
- 36. Ghosh A, Greenberg ME. (1995) Distinct roles for bFGF and NT‐3 in the regulation of cortical neurogenesis. Neuron 15:89–103. [DOI] [PubMed] [Google Scholar]
- 36a. Goldman SA, Luskin MB. (1998) Strategies utilized by migrating neurons of the postnatal vertebrate forebrain, Trends Neurosci 21:107–114. [DOI] [PubMed] [Google Scholar]
- 37. Gritti A, Parati EA, Cova L, Frölichsthal P, Galli R, Wanke E, Faravelli L, Morassutti DJ, Roisen F, Nickel DD, Vescovi AL. (1996) Multipotential stem cells from the adult mouse brain proliferate and self‐renew in response to basic fibroblast growth factor. J Neurosci 16:1091–1100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Gross RE, Meheler Zang Z, Santschi L, Kessler J. (1996) Bone morphogenetic proteins promote astroglial lineage commitment by mammalian subventricular zone progenitor cells. Neuron 17:595–606. [DOI] [PubMed] [Google Scholar]
- 39. Groves AK, Barnett SC, Franklin RJM, Crang AJ, Mayer M, Blakemore WF, Noble M. (1993) Repair of demyelinated lesions by transplantation of purified O‐2A progenitor cells. Nature 362:453–455. [DOI] [PubMed] [Google Scholar]
- 40. Himes BT, Slowska‐Baird J, Boyne L, Snyder EY, Tessler A, Fischer I. (1995) Grafting of genetically modified cells that produce neurotrophins in order to rescue axotomized neurons in rat spinal cord. Soc Neurosci Abstr 21:537. [Google Scholar]
- 41. Iavarone A, Massague J. (1997) Repression of the CDK activator Cdc25A and cell‐cycle arrest by cytokine TGF‐b in cells lacking the CDK inhibitor p15. Nature 387:417–422. [DOI] [PubMed] [Google Scholar]
- 42. Jacobson M. (1995) Developmental Neurobiology 3rd edition. Plenum Press, New York and London . [Google Scholar]
- 43. Jensen AM, Raff M. (1997) Continual observation of multipotential retinal progenitors in clonal density cultures. Dev Biol 188:267–279. [DOI] [PubMed] [Google Scholar]
- 44. Johe KK, Hazel TG, Muller T, Dugich‐Djordjevic MM, McKay RDG. (1996) Single factors direct the differentiation of stem cells from fetal and adult nervous system. Genes Dev 10:3129–3140. [DOI] [PubMed] [Google Scholar]
- 45. Kilpatrick TJ, Richards LJ, Bartlett PF. (1995) The regulation of neural precursor cells within the mammalian brain. Molec Cell Neurosci 6:2–15. [DOI] [PubMed] [Google Scholar]
- 46. Kilpatrick TJ, Bartlett PF. (1995) Cloned multipotential precursors from the mouse cerebrum require FGF‐2, whereas glial restricted precursors are stimulated with either FGF‐2 or EGF. J Neurosci 5:3653–3661. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Kirschenbaum B, Nedergaard M, Preuss A, Barami K, Fraser RA, Goldman SA. (1994) In vitro neuronal production and differentiation by precursor cells derived from the adult human forebrain. Cerebral Cortex 6:576–589. [DOI] [PubMed] [Google Scholar]
- 47a. Kitchens DL, Snyder EY, Gottlieb Dl. (1994) bFGF & EGF are mitogens for immortalized neural progenitors. J Neurobiol 25:797–807. [DOI] [PubMed] [Google Scholar]
- 48. Kuhn HG, Winkler J, Kempermann G, Thai LJ, Gage FH. (1997) Epidermal Growth Factor and Fibroblast Growth Factor‐2 have different effects on neural progenitors in the adult rat brain. J Neurosci 17:5820–5828. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49. Lacorazza HD, Flax JD, Snyder EY, Jendoubi M. (1996) Expression of human _b‐hexosaminidase alfa‐subunit gene (the gene defect of Tay‐Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat Med 2:424–429. [DOI] [PubMed] [Google Scholar]
- 50. Leber SM, Breedlove M, Sanes JR. (1990) Lineage arrangement and death of motoneurons in the chicken spinal cord. J Neurosci 10:2451–2462. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Lendahl U, Zimmerman LB, McKay RDG. (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60:585–595. [DOI] [PubMed] [Google Scholar]
- 52. Levison SW, Goldman JE. (1997) Multipotential and lineage restricted precursors coexist in the mammalian perinatal subventricular zone. J Neurosci Res 48:83–94. [PubMed] [Google Scholar]
- 53. Lillien L. (1998) Neural Progenitors and stem cells: mechanisms of progenitor heterogeneity. Curr Opin Neurobiol 8 (1):37–44. [DOI] [PubMed] [Google Scholar]
- 54. Lim DA, Fishell GJ, Alvarez‐Buylla A. (1997) Postnatal mouse subventricular zone neuronal precursors can migrate and differentiate within multiple levels of the developing neuraxis. Proc Natl Acad Sci USA 94:14832–14836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54a. Liu Y, Himes BT, Chow SY, Park KI, Tessler A, Snyder EY, Fischer I, Intraspinal delivery of neurotrophin‐3 (NT‐3) using neural stem cells genetically modified by recombinant retrovirus Exp Neurol (in press). [DOI] [PubMed] [Google Scholar]
- 55. Loeffler M, Potten CS. (1997) Stem cells and cellular pedigrees ‐ a conceptual introduction, pp 1–27 in Stem Cells. Potten CS. (ed) Academic Press, San Diego ( CA ). [Google Scholar]
- 56. Lois C, Alvarez‐Buylla A. (1993) Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci USA 90:2074–2077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57. Lois C, Alvarez‐Buylla A. (1994) Long‐distance neuronal migration in the adult mammalian brain. Science 264:1145–1148. [DOI] [PubMed] [Google Scholar]
- 58. Lundberg C, Bjorklund A. (1996) Host regulation of glial markers in intrastriatal grafts of conditionally immortalized neural stem cell lines. Neuroreport 7:847–852. [DOI] [PubMed] [Google Scholar]
- 59. Lundberg C, Field PM, Ajayi YO, Raisman G, Bjorklund A. (1996a) Conditionally immortalized neural progenitor cell lines integrate and differentiate after grafting to the adult rat striatum: a combined autoradiographic and electron microscopic study. Brain Res 737:295–300. [DOI] [PubMed] [Google Scholar]
- 60. Lundberg C, Martinez‐Serrano A, Cattaneo E, McKay RDG, Bjorklund A. (1997) Survival, integration and differentiation of neural stem cell lines after transplantation to the adult rat striatum. Exp Neurol In press. [DOI] [PubMed] [Google Scholar]
- 61. Luskin MB, Pearlman AL, Sanes JR. (1988) Cell lineage in the cerebral cortex of the mouse studied in vitro and in vivo with a recombinant retrovirus. Neuron 1:635–647. [DOI] [PubMed] [Google Scholar]
- 62. Luskin MB. (1993) Restricted proliferation and migration of post‐natal generated neurons derived from the fore‐brain subventricular zone. Neuron 11:173–189. [DOI] [PubMed] [Google Scholar]
- 63. Lynch WP, Snyder EY, Qualtiere L, Portis JL, Sharpe AH. (1996) Late virus replication events in microglia are required for neurovirulent retrovirus‐induced spongiform neurodegeneration: evidence from neural progenitor‐derived chimeric mouse brains. J Virol 70: 8896–8907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63a. Lynch WP, Sharpe AH, Snyder EY (1999) Neural stem cells as engraftable packaging lines can optimize viral vector‐mediated gene delivery to the CNS evidence from studying retroviral env‐related neurodegeneration. J Virol. (in Press). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64. Martinez‐Serrano A, Fischer W, Bjorklund A. Reversal of age‐dependent cognitive impairments and cholinergic neuron atrophy by NGF‐secreting neural progenitors grafted to the basal forebrain. Neuron 15:473–484. [DOI] [PubMed] [Google Scholar]
- 65. Martinez‐Serrano A, Lundber C, Horellou P, Fischer W, Bentlage C, Campbell K, McKay RDG, Mallet J, Bjorklund A. (1995) CNS‐derived neural progenitor cells for gene transfer of nerve growth factor to the adult rat brain: complete rescue of axotomized cholinergic neurons after implantation into the septum. J Neurosci 15:5668–5680. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66. Martinez‐Serrano A, Bjorklund A. (1996) Protection of the neostriatum against excitotoxic damage by neurotrophin‐producing genetically modified neural stem cells. J Neurosci 16:4604–4616. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67. Martinez‐Serrano A, Bjorklund A. (1996) Gene transfer to the mammalian brain using neural stem cells. Focus on trophic factors, neuro‐regeneration and cholinergic neuron systems. Clin Neurosci 3:301–309. [PubMed] [Google Scholar]
- 67a. Martinez‐Serrano A, Snyder EY (1998), Neural stem cell lines for CNS repair, in CNS Regeneration: Basic Science & Clinical Applications (eds, Tuszynski M, Kordower J) Academic Press, San Diego pp. 203–250. [Google Scholar]
- 68. Martinez‐Serrano A, Fischer W, Soderstrom S, Ebendal T, Bjorklund A. (1996) Long term functional recovery from age‐induced spatial memory impairments by nerve growth factor gene transfer to the rat basal forebrain. Proc Natl Acad Sci USA 93:6355–6360. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69. Martinez‐Serrano A, Bjorklund A. (1997) Immortalized neural progenitor cells for CNS gene transfer and repair. Trends Neurosci 20:530–538. [DOI] [PubMed] [Google Scholar]
- 70. Mayer‐Proschel M., Kalyani AJ, Mujtaba T, Rao MS. (1997) Isolation of lineage‐restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron 19(4):773–785. [DOI] [PubMed] [Google Scholar]
- 71. McCarthy KD, De Vellis J. (1980) Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85:890–902. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72. McConnel SK (1995) Constructing the cerebral cortex: neurogenesis and fate determination. Neuron 15: 761–768. [DOI] [PubMed] [Google Scholar]
- 73. McKay RDG. (1992) Immortal mammalian neuronal stem cells differentiate after implantation into the developing brain In: Gene transfer and therapy in the nervous system, Gage FH and Christen Y, eds, pp 76–85. Springer‐Verlag, Berlin – Heidelberg . [Google Scholar]
- 74. McKay R. (1997) Stem cells in the central nervous system. Science 276:66–71. [DOI] [PubMed] [Google Scholar]
- 75. Morrison SJ, Shah NM, Anderson DJ. (1997) Regulatory mechanisms in stem cell biology. Cell 88:287–298. [DOI] [PubMed] [Google Scholar]
- 76. Morshead CM, van der Kooy D. (1992) Postmitotic death is the fate of consitutively proliferating cells in the subependymal layer of the adult mouse brain. J Neurosci 12:249–256. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77. Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, Weiss S, van der Kooy D. (1994) Neural stem cell in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron 13:1071–1082. [DOI] [PubMed] [Google Scholar]
- 78. Murray K, Dubois‐Dalcq M. (1997) Emergence of oligodendrocytes from human neural spheres. J Neurosci Res 50:146–156. [DOI] [PubMed] [Google Scholar]
- 79. Nourse J (1994) Interleukin‐2‐mediated elimination of the p27kip‐1 cyclin‐dependent kinase inhibitor prevented by rapamycin. Nature 372:570–573. [DOI] [PubMed] [Google Scholar]
- 80. Olanow CW, Kordower JH, Freeman TB. (1996) Foetal nigral transplantation as a therapy for Parkinson's disease. Trends Neurosci 19:102–109. [DOI] [PubMed] [Google Scholar]
- 81. Ono K, Yasui Y, Rutishauser U, Miller RH. (1997) Focal origin and migration of oligodendrocyte precursors into the chick optic nerve. Neuron 19:283–292. [DOI] [PubMed] [Google Scholar]
- 82. Palmer TD, Ray J, Gage FH. (1995) FGF‐2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 6:474–486. [DOI] [PubMed] [Google Scholar]
- 83. Park KI, Jensen FE, Snyder EY (1995) Neural progenitor transplantation for hypoxic‐ischemic brain injury in immature mice. Soc Neurosci Abstr 21, 2027. [Google Scholar]
- 84. Park KI, Jensen FE, Stieg PE, Fischer I, Snyder EY. (1997) Transplantation of neural stem‐like cells engineered to produce NT‐3 may enhance neuronal replacement in hypoxia‐ischemia CNS injury. Soc Neurosci Abstr 23:346. [Google Scholar]
- 84a. Park KI, Liu S, Flax JD, Nissim S, Stieg PE, Snyder EY. (1999) Transplantation of neural progenitor & stem‐like cells: developmental insights may suggest new therapies for spinal cord & other CNS dysfunction, J Neurotrauma (in press). [DOI] [PubMed] [Google Scholar]
- 85. Peschanski M, Cesaro P, Hantraye P. (1995) Rationale for intrastriatal grafting of striatal neuroblasts in patients with Huntington's disease. Neurosci 68:273–285. [DOI] [PubMed] [Google Scholar]
- 86. Pincus DW, Keyoung HM, Harrison‐Restelli C, Goodman RR, Fraser RA, Edgar M, Sakakibara MS, Okano H, Nederegaard M, Goldman SA. (1998) FGF2/BDNF‐associated maturation of new neurons generated from adult human subependymal cells. Ann Neurol 43:576–585. [DOI] [PubMed] [Google Scholar]
- 87. Price J, Thurlow L. (1988) Cell lineage in the rat cerebral cortex: a study using retroviral mediated gene transfer. Development 104:473–482. [DOI] [PubMed] [Google Scholar]
- 88. Qian X, Davis AA, Goderie SK, Temple S. (1997) FGF2 concentration regulated the generation of neurons and glia from multipotent cortical stem cells. Neuron 18:81–93. [DOI] [PubMed] [Google Scholar]
- 89. Quesenberry P, Levitt P (1979) Hematopoetic stem cells. N Eng J Med 301:755–766, 819–823, 868–872. [DOI] [PubMed] [Google Scholar]
- 90. Reid CB, Liang I, Walsh C. (1995) Systematic widespread clonal organization in the cerbral cortex. Neuron 15:299–310. [DOI] [PubMed] [Google Scholar]
- 91. Renfranz PJ, Cunningham MG, McKay RDG. (1991) Region‐specific differentiation of the hippocampal stem cell line HiB5 upon implantation into the developing mammalian brain. Cell 66:713–729. [DOI] [PubMed] [Google Scholar]
- 92. Reynolds BA, Weiss S. (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710. [DOI] [PubMed] [Google Scholar]
- 93. Reynolds B.A., Tetzlaff W, Weiss S. (1992) A multipotent EGF‐responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12: 4565–4574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94. Reynolds BA, Weiss S. (1996) Clonal and population analyses demonstrate that an EGF‐responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 175:1–13. [DOI] [PubMed] [Google Scholar]
- 95. Richards LJ, Kilpatrick TJ, Bartlett PF. (1992) De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci USA 89 (18):8591–8595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96. Ryder EF, Snyder EY, Cepko CL. (1990) Establishment and characterization of multipotent neural cell lines using retrovirus vector‐mediated oncogene trasnfer. J Neurobiol 21:356–375. [DOI] [PubMed] [Google Scholar]
- 97. Sabaate O, Horellou P, Vigne E, et al. (1995) Transplantation to the rat brain of human neural progenitors that were genetifcally modified using adenoviruses. Nat Gen 9:256–260. [DOI] [PubMed] [Google Scholar]
- 98. Sah DWY, Ray J, Gage FH. (1997) Bipotent progenitor cell lines from the human CNS. Nat Biotech 15:574–580. [DOI] [PubMed] [Google Scholar]
- 99. Snyder EY, Deitcher DL, Walsh C, Arnold‐Aldea S, Hartwieg EA, Cepko CL. (1992) Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 68:33–55. [DOI] [PubMed] [Google Scholar]
- 100. Snyder EY, Yandava BD, Pan Z‐H, Yoon C, Macklis JD. (1993) Immortalized postnatally‐derived cerebellar progenitors can engraft and participate in development of multiple structures at multiple stages along mouse neuraxis. Soc Neurosci Abstr 19:613. [Google Scholar]
- 101. Snyder EY. (1994) Grafting immortalized neurons to the CNS. Curr Opin Neurobiol 4:742–751. [DOI] [PubMed] [Google Scholar]
- 102. Snyder EY. (1995) Retroviral vectors for the study of neuroembryology: immortalization of neural cells In: Kaplit MG and Loewy AD, editors Viral Vectors: Tools for analysis and genetic manipulation of the Nervous System. New York : Academic Press; pp:435–475. [Google Scholar]
- 103. Snyder EY, Flax JD. (1995) Transplantation of neural progenitors and stem‐like cells as a strategy for gene therapy and repair of neurodegenerative diseases. Mental Retard Develop Disabil Res Rev 1:27–38. [Google Scholar]
- 104. Snyder EY, Taylor RM, Wolfe JH. (1995) Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 374:367–370. [DOI] [PubMed] [Google Scholar]
- 105. Snyder EY. (1995b) Immortalized neural stem cells: insights into development; prospects for gene therapy and repair. Proc Assoc Am Physicians 107:195–204. [PubMed] [Google Scholar]
- 106. Snyder EY. (1995) Retroviral vectors for the study of neuroembryology: immortalization of neural cells In: Kaplit MG and Loewy AD, eds. Viral vectors: tools for analysis and genetic manipulation of the nervous system. New York : Academic Press, pp: 435–475. [Google Scholar]
- 107. Snyder EY, Macklis JD. (1996) Multipotent neural progenitor or stem‐like cells may be uniquely suited for therapy for some neurodegenerative conditions. Clin Neurosci 3:310–316. [PubMed] [Google Scholar]
- 108. Snyder EY, Fisher LJ. (1996) Gene therapy for neurologic diseases. Curr Opin Pediatr 8:558–568. [DOI] [PubMed] [Google Scholar]
- 109. Snyder EY, Wolfe JH. (1996) CNS cell transplantation: a novel therapy for storage diseases Curr Opin Neurol 9:126–136. [DOI] [PubMed] [Google Scholar]
- 110. Snyder EY, Flax JD, Yandava BD, Park KI, Liu S, Rosario CM, Aurora S. (1997) Transplantation and differentiation of neural “stem‐like” cells: possible insights into development and therapeutic potential In: Gage FH, Christen Y, editors Research and Perspectives in Neurosciences: Isolation, Characterization, and Utilization of CNS Stem Cells. Springer‐Verlag; pp:173–196. [Google Scholar]
- 111. Snyder EY, Park KI, Flax JD, et al. (1997) The potential of neural “stem‐like” cells for gene therapy and repair of the degenerating CNS In: Seil, F J , editor. Advances in Neurology: Neuronal Regeneration, Reorganization, and Repair. New York : Raven Press, pp:121–132. [PubMed] [Google Scholar]
- 112. Snyder EY, Senut M‐C. (1997) Use of non‐neuronal cells for gene delivery. Neurobiol Dis 4:69–102. [DOI] [PubMed] [Google Scholar]
- 113. Snyder EY, Yoon C, Flax JD, Macklis JD. (1997) Multipotent neural progenitors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex. Proc Natl Acad Sci USA 94:11645–11650. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 114. Snyder EY. (1998) Neural stem‐like cells: developmental lessons with therapeutic potential. The Neuroscientist 4(6):408–425. [Google Scholar]
- 115. Steiner P (1995) Identification of a Myc‐dependent step during the formation of active G1 cyclin‐cdk complexes. EMBO J 14:4814–4826. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116. Stemple DL, Mahantappa NK. (1997) Neural stem cells are blasting off. Neuron 18:1–4. [DOI] [PubMed] [Google Scholar]
- 117. Studer L, Tabar V, McKay R (1998) Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat Neurosci 1 (4):290–295. [DOI] [PubMed] [Google Scholar]
- 118. Suhonen JO, Peterson DA, Ray J, Gage FH (1996) Differentiation of adult hippocampus‐derived progenitors into olfactory neurons in vivo. Nature 383: 624–627. [DOI] [PubMed] [Google Scholar]
- 119. Suhr S, Gage FH. (1993) Gene therapy for neurologic disease. Arch Neurol 50:1252–1268. [DOI] [PubMed] [Google Scholar]
- 120. Svendsen CN, Clarke DJ, Rosser AE, Dunnett SB. (1996) Survival and differentiation of rat and human epidermal growth factor‐responsive precursor cells following grafting into the lesioned adult central nervous system. Exp Neurol 137:376–388. [DOI] [PubMed] [Google Scholar]
- 121. Svendsen CN, Caldwell MA, Shen J, ter Borg MG, Rosser AE, Karmiol S, Dunnet SB. (1997) Long‐term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson's disease. Exp Neurol 148:135–146. [DOI] [PubMed] [Google Scholar]
- 122. Temple S, Qian X. (1996) Vertebrate neural progenitors: subtypes and regulation. Curr Opin Neurobiol 6:11–17. [DOI] [PubMed] [Google Scholar]
- 123. Trojanowski JQ, Kleppner SR, Hartley RS, Miyazono M, Fraser NW, Kesari S, Lee VM. (1997) Transfectable and transplantable postmitotic human neurons: a potential platform for gene therapy of nervous sytem diseases. Exp Neurol 144:92–97. [DOI] [PubMed] [Google Scholar]
- 124. Turner DL, Cepko CL. (1987) A common progenitor for neurons and glia persists in rat retina late in development. Nature 328:131–136. [DOI] [PubMed] [Google Scholar]
- 125. Turner DL, Snyder EY, Cepcko CL. (1990) Lineage independent determination of cell type in the embryonic mouse retina. Neuron 4:833–845. [DOI] [PubMed] [Google Scholar]
- 126. Vescovi AL, Reynolds BA, Fraser DD, Weiss S. (1993) bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF‐generated CNS progenitor cells. Neuron 11:951–966. [DOI] [PubMed] [Google Scholar]
- 127. Vescovi AL, Daadi M, Asham R, Reynolds BA. (1997) Continuous generation of human catecholaminergic neurons by embryonic CNS stem cells. Vol. 23 (I). In 27th Meeting Soc. Neurosci.: New Orleans Louisiana, Abs 131.6 pp:319. [Google Scholar]
- 128. Vescovi AL, Parati EA, Gritti A, Poulin P, Wanke E, Frölichsthal‐Schoeller P, Cova L, Arcellana‐Panlilio M, Colombo A, Galli R. (1999) Isolation and cloning of multipotential stem cells from the embryonic human CNS and establishment of transplantable human neural stem cell lines by epigenetic stimulation. Exp Neurol 156:71–83. [DOI] [PubMed] [Google Scholar]
- 128a. Wagner J, Akerud P, Castro D, Holm PC, Snyder EY, Perlmann T, Arenas E (1999) Type 1 astrocytes induce a midbrain dopaminergic phenotype in Nurr‐1‐overexpressing neural stem cells, Nature Biotech (in press). [DOI] [PubMed] [Google Scholar]
- 129. Walsh C, Cepcko CL. (1992) Widspread dispersion of neuronal clones across functional regions of the cerebral cortex. Science 255:434–440. [DOI] [PubMed] [Google Scholar]
- 130. Weiss S, Dunne C, Hewson J, Wohl C, Wheatley M, Peterson AC, Reynolds BA. (1996) Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuraxis. J Neurosci 16:7599–7609. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 131. Weiss S, Reynolds BA, Vescovi AL, Morshead C, van der Kooy D. (1996) Is there a neural stem cell in the mammalian forebrain Trends Neurosci 19:387–393. [DOI] [PubMed] [Google Scholar]
- 132. Weissman IL. Stem cells: the lessons from hematopoieses. (1997) In: Gage F, Christen Y editors Isolation, characterization, and utilization of CNS stem cells. Berlin Heidelberg : Springer‐Verlag; pp:1–8. [Google Scholar]
- 133. White L, Whittemore SR. (1992) Immortalization of raphe neurons: an approach to neuronal function in vitro and in vivo. J Chem Neuroanatomy 5:327–330. [DOI] [PubMed] [Google Scholar]
- 134. White LA, Eaton MJ, Castro MC, Klose J, Globus MY‐T, Shaw G, Whittemore SR. (1994) Distinct regulatory pathways control neurofilament expression and neurotransmitter synthesys in immortalized serotonergic neurons. J Neurosci 14:6744–6753. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 135. Whittemore SR, Snyder EY. (1996) Physiological significance and functional potential of central nervous system‐derived cell lines. Mol Neurobiol 12:13–38. [DOI] [PubMed] [Google Scholar]
- 136. Wichterle H, Garcia‐Verdugo JM, Alvarez‐Buylla A. (1997) Direct evidence for homotopic, glia‐independent neuronal migration. J Neurosci 18:779–791. [DOI] [PubMed] [Google Scholar]
- 137. Williams BP, Price J. (1995) Evidence for multiple precursor types in the embryonic rat cerebral cortex. Neuron 14:1181–1188. [DOI] [PubMed] [Google Scholar]
- 138. Winkler C, Fricker RA, Gates MA, Olsson M, Hammang JP, Carpenter MK, Bjorklund A. (1998) Incorporation and glial differentiation of mouse EGF‐responsive neural progenitor cells after transplantation into the embryonic rat brain. Mol Cell Neurosci 11 (3):99–116. [DOI] [PubMed] [Google Scholar]
- 138a. Yamanaka S, Johnson MD, Grinberg A, Westphal H, Crawley JN, Taniike M, Suzuki K, Proia RL. (1994) Targeted disruption of the HexA gene results in mice with biochemical and pathologic features of Tay‐Sachs disease, Proc Natl Acad Sci USA 91:9975–9979. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 139. Yandava BD, Billinghurst LL, Snyder EY. (1999) “Global” cell replacement is feasible via neural stem cell transplantation: evidence from the shiverer dysmyelinated mouse brain, Proc Natl Acad Sci USA (in press). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 140. Yuen EC, Mobley WC. (1996) Therapeutic potential of neurotrophic factors for neurological disorders. Ann Neurol 40:346–354. [DOI] [PubMed] [Google Scholar]
- 141. Zang W, Lee WH, Triarhou LC. (1996) Grafted cerebellar cells in a mouse model of hereditary ataxia express IGF‐1 system genes and partially restore behavoural function. Nat Med 2:65–71. [DOI] [PubMed] [Google Scholar]
- 142. Zawada WM, Cibelli JB, Choi PK, Clarkson ED, Golueke PJ, Witta SE, Bell KP, Kane J, Ponce de Leon FA, Jerry DJ, Robl JM, Freed CR, Stice SL. (1998) Somatic cell cloned transgenic bovine neurons for transplantation in parkinsonian rats. Nat Med 4 (5):569–574. [DOI] [PubMed] [Google Scholar]
- 143. Zlomanczuk P, Mruggala M, de la Iglesia H, Quesenberry PJ, Snyder EY, Schwartz WJ. (1999) Appropriate response to a natural photic stimulus by transplanted clonal neural stem cells following incorporation within the suprachiastmatic nucleus (submitted). [DOI] [PubMed]