Skip to main content
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;6(4):475–496. doi: 10.1111/j.1582-4934.2002.tb00451.x

Neural stem cells in aging and disease

T L Limke 1,, Mahendra S Rao 1
PMCID: PMC6741307  PMID: 12611637

Abstract

Aging in the central nervous system is associated with progressive loss of function which is exacerbated by neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. The two primary cell replacement strategies involve transplantation of exogenous tissue, and activation of proliferation of endogenous cells. Transplanted tissue is used to either directly replace lost tissue, or to implant genetically engineered cells that secrete factors which promote survival and/or proliferation. However, successful application of any cell replacement therapy requires knowledge of the complex relationships between neural stem cells and the more restricted neural and glial progenitor cells. This review focuses on recent advances in the field of stem cell biology of the central nervous system, with an emphasis on cellular and molecular approaches to replacing cells lost in neurodegenerative disorders.

Keywords: neural stem cell, Alzheimer's, Parkinson's, stroke, aging

References

  • 1. Kemper T., Neuroanatomical and neuropathological changes during aging and in dementia In: Albert M., Knoepfel J., eds., Clinical Neurology of Aging, Oxford University Press, New York , 1994, pp. 3–67. [Google Scholar]
  • 2. Cowell P.E., Turetsky B.I., Gur R.C., Grossman R.I., Shtasel D.L., Gur R.E., Sex differences in aging of the human frontal and temporal lobes, J. Neurosci., 14: 4748–4755, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Raz N., Gunning F.M., Head D., Dupuis J.H., McQuain J., Briggs S.D., Loken W.J., Thornton A.E., Acker J.D., Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter, Cereb. Cortex., 7: 268–282, 1997. [DOI] [PubMed] [Google Scholar]
  • 4. Raz N., Torres I.J., Acker J.D., Age, gender, and hemispheric differences in human striatum: a quantitative review and new data from in vivo MRI morphometry, Neurobiol. Learn. Mem., 63: 133–142, 1995. [DOI] [PubMed] [Google Scholar]
  • 5. Doraiswamy P.M., Na C., Husain M.M., Figiel G.S., McDonald W.M., Ellinwood E.H., Jr. , Boyko O.B., Krishnan K.R., Morphometric changes of the human midbrain with normal aging: MR and stereologic findings, AJNR Am. J. Neuroradiol., 13: 383–386, 1992. [PMC free article] [PubMed] [Google Scholar]
  • 6. Weis S., Kimbacher M., Wenger E., Neuhold A., Morphometric analysis of the corpus callosum using MR: correlation of measurements with aging in healthy individuals, AJNR Am. J. Neuroradiol., 14: 637–645, 1993. [PMC free article] [PubMed] [Google Scholar]
  • 7. Trollor J.N., Valenzuela M.J., Brain ageing in the new millennium, Aust N Z J Psychiatry, 35: 788–805, 2001. [DOI] [PubMed] [Google Scholar]
  • 8. Morrison J.H., Hof P.R., Life and death of neurons in the aging brain, Science, 278: 412–9, 1997. [DOI] [PubMed] [Google Scholar]
  • 9. Bertoni‐Freddari C., Fattoretti P., Paoloni R., Caselli U., Galeazzi L., Meier‐Ruge W., Synaptic structural dynamics and aging, Gerontology, 42: 170–180, 1996. [DOI] [PubMed] [Google Scholar]
  • 10. Mattson M.P., Pedersen W.A., Duan W., Culmsee C., Camandola S., Cellular and molecular mechanisms underlying perturbed energy metabolism and neuronal degeneration in Alzheimer's and Parkinson's diseases, Ann. N. Y. Acad. Sci., 893: 154–175, 1999. [DOI] [PubMed] [Google Scholar]
  • 11. Sastre J., Pallardo F.V., Vina J., Mitochondrial oxidative stress plays a key role in aging and apoptosis, IUBMB Life, 49: 427–435, 2000. [DOI] [PubMed] [Google Scholar]
  • 12. Schapira A.H., Oxidative stress and mitochondrial dysfunction in neurodegeneration, Curr. Opin. Neurol., 9: 260–264, 1996. [DOI] [PubMed] [Google Scholar]
  • 13. Keller J.N., Mattson M.P., Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system, Rev. Neurosci., 9: 105–116, 1998. [DOI] [PubMed] [Google Scholar]
  • 14. Reuter‐Lorenz P., New visions of the aging mind and brain, Trends Cogn. Sci., 6: 394, 2002. [DOI] [PubMed] [Google Scholar]
  • 15. Mattson M.P., Brain evolution and lifespan regulation: conservation of signal transduction pathways that regulate energy metabolism, Mech. Ageing Dev., 123: 947–953, 2002. [DOI] [PubMed] [Google Scholar]
  • 16. Bartke A., Brown‐Borg H.M., Bode A.M., Carlson J., Hunter W.S., Bronson R.T., Does growth hormone prevent or accelerate aging?, Exp. Gerontol., 33: 675–687, 1998. [DOI] [PubMed] [Google Scholar]
  • 17. Flurkey K., Papaconstantinou J., Miller R.A., Harrison D.E., Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production, Proc. Natl. Acad. Sci. U S A, 98: 6736–6741, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Honda Y., Honda S., The daf‐2 gene network for longevity regulates oxidative stress resistance and Mn‐superoxide dismutase gene expression in Caenorhabditis elegans , Faseb J., 13: 1385–1393, 1999. [PubMed] [Google Scholar]
  • 19. Lin K., Hsin H., Libina N., Kenyon C., Regulation of the Caenorhabditis elegans longevity protein DAF‐16 by insulin/IGF‐1 and germline signaling, Nat. Genet., 28: 139–145, 2001. [DOI] [PubMed] [Google Scholar]
  • 20. Wolkow C.A., Kimura K.D., Lee M.S., Ruvkun G., Regulation of C. elegans life‐span by insulinlike signaling in the nervous system, Science, 290: 147–150, 2000. [DOI] [PubMed] [Google Scholar]
  • 21. Kalyani A.J., Mujtaba T., Rao M.S., Expression of EGF receptor and FGF receptor isoforms during neuroepithelial stem cell differentiation, J. Neurobiol., 38: 207–224, 1999. [PubMed] [Google Scholar]
  • 22. Quinn S.M., Walters W.M., Vescovi A.L., Whittemore S.R., Lineage restriction of neuroepithelial precursor cells from fetal human spinal cord, J. Neurosci. Res., 57: 590–602, 1999. [PubMed] [Google Scholar]
  • 23. Ling Z.D., Potter E.D., Lipton J.W., Carvey P.M., Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines, Exp. Neurol., 149: 411–423, 1998. [DOI] [PubMed] [Google Scholar]
  • 24. Roy N.S., Benraiss A., Wang S., Fraser R.A., Goodman R., Couldwell W.T., Nedergaard M., Kawaguchi A., Okano H., Goldman S.A., Promoter‐targeted selection and isolation of neural progenitor cells from the adult human ventricular zone, J. Neurosci. Res., 59: 321–331, 2000. [DOI] [PubMed] [Google Scholar]
  • 25. Roy N.S., Wang S., Jiang L., Kang J., Benraiss A., Harrison‐Restelli C., Fraser R.A., Couldwell W.T., Kawaguchi A., Okano H., Nedergaard M., Goldman S.A., In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus, Nat. Med., 6: 271–277, 2000. [DOI] [PubMed] [Google Scholar]
  • 26. Song H.J., Stevens C.F., Gage F.H., Neural stem cells from adult hippocampus develop essential properties of functional CNS neurons, Nat. Neurosci., 5: 438–445, 2002. [DOI] [PubMed] [Google Scholar]
  • 27. Li R., Thode S., Zhou J., Richard N., Pardinas J., Rao M.S., Sah D.W., Motoneuron differentiation of immortalized human spinal cord cell lines, J. Neurosci. Res., 59: 342–352, 2000. [DOI] [PubMed] [Google Scholar]
  • 28. Sato K., Hayashi T., Sasaki C., Iwai M., Li F., Manabe Y., Seki T., Abe K., Temporal and spatial differences of PSA‐NCAM expression between young‐adult and aged rats in normal and ischemic brains, Brain Res., 922: 135–139, 2001. [DOI] [PubMed] [Google Scholar]
  • 29. Scolding N.J., Rayner P.J., Compston D.A., Identification of A2B5‐positive putative oligodendrocyte progenitor cells and A2B5‐positive astrocytes in adult human white matter, Neuroscience, 89: 1–4, 1999. [DOI] [PubMed] [Google Scholar]
  • 30. Prabhakar S., D'Souza S., Antel J.P., McLaurin J., Schipper H.M., Wang E., Phenotypic and cell cycle properties of human oligodendrocytes in vitro, Brain Res., 672: 159–169, 1995. [DOI] [PubMed] [Google Scholar]
  • 31. Rao M.S., Mayer‐Proschel M., Glial‐restricted precursors are derived from multipotent neuroepithelial stem cells, Dev. Biol., 188: 48–63, 1997. [DOI] [PubMed] [Google Scholar]
  • 32. Mi H., Barres B.A., Purification and characterization of astrocyte precursor cells in the developing rat optic nerve, J. Neurosci., 19: 1049–1061, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. Seidman K.J., Teng A.L., Rosenkopf R., Spilotro P., Weyhenmeyer J.A., Isolation, cloning and characterization of a putative type‐1 astrocyte cell line, Brain Res., 753: 18–26, 1997. [DOI] [PubMed] [Google Scholar]
  • 34. Laywell E.D., Rakic P., Kukekov V.G., Holland E.C., Steindler D.A., Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain, Proc. Natl. Acad. Sci. USA, 97: 13883–13888, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Kondo T., Raff M., Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells, Science, 289: 1754–1757, 2000. [DOI] [PubMed] [Google Scholar]
  • 36. Sommer L., Rao M., Neural stem cells and regulation of cell number, Prog. Neurobiol., 66: 1–18, 2002. [DOI] [PubMed] [Google Scholar]
  • 37. McMahon J.A., Takada S., Zimmerman L.B., Fan C.M., Harland R.M., McMahon A.P., Noggin‐mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite, Genes Dev., 12: 1438–1452, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Lim D.A., Tramontin A.D., Trevejo J.M., Herrera D.G., Garcia‐Verdugo J.M., Alvarez‐Buylla A., Noggin antagonizes BMP signaling to create a niche for adult neurogenesis, Neuron, 28: 713–726, 2000. [DOI] [PubMed] [Google Scholar]
  • 39. Palmer T.D., Markakis E.A., Willhoite A.R., Safar F., Gage F.H., 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, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Whittemore S.R., Morassutti D.J., Walters W.M., Liu R.H., Magnuson D.S., Mitogen and substrate differentially affect the lineage restriction of adult rat subventricular zone neural precursor cell populations, Exp. Cell Res., 252: 75–95, 1999. [DOI] [PubMed] [Google Scholar]
  • 41. Pincus D.W., Keyoung H.M., Harrison‐Restelli C., Goodman R.R., Fraser R.A., Edgar M., Sakakibara S., Okano H., Nedergaard M., Goldman S.A., Fibroblast growth factor‐2/brainderived neurotrophic factor‐associated maturation of new neurons generated from adult human subependymal cells, Ann. Neurol., 43: 576–585, 1998. [DOI] [PubMed] [Google Scholar]
  • 42. Shetty A.K., Turner D.A., In vitro survival and differentiation of neurons derived from epidermal growth factor‐responsive postnatal hippocampal stem cells: inducing effects of brain‐derived neurotrophic factor, J. Neurobiol., 35: 395–425, 1998. [DOI] [PubMed] [Google Scholar]
  • 43. Smith A.G., Heath J.K., Donaldson D.D., Wong G.G., Moreau J., Stahl M., Rogers D., Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides, Nature, 336: 688–690, 1988. [DOI] [PubMed] [Google Scholar]
  • 44. Williams R.L., Hilton D.J., Pease S., Willson T.A., Stewart C.L., Gearing D.P., Wagner E.F., Metcalf D., Nicola N.A., Gough N.M., Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells, Nature, 336: 684–687, 1988. [DOI] [PubMed] [Google Scholar]
  • 45. Conover J.C., Ip N.Y., Poueymirou W.T., Bates B., Goldfarb M.P., DeChiara T.M., Yancopoulos G.D., Ciliary neurotrophic factor maintains the pluripotentiality of embryonic stem cells, Development, 119: 559–565, 1993. [DOI] [PubMed] [Google Scholar]
  • 46. Yoshida K., Chambers I., Nichols J., Smith A., Saito M., Yasukawa K., Shoyab M., Taga T., Kishimoto T., Maintenance of the pluripotential phenotype of embryonic stem cells through direct activation of gp130 signalling pathways, Mech. Dev., 45: 163–171, 1994. [DOI] [PubMed] [Google Scholar]
  • 47. Hughes S.M., Lillien L.E., Raff M.C., Rohrer H., Sendtner M., Ciliary neurotrophic factor induces type‐2 astrocyte differentiation in culture, Nature, 335: 70–73, 1988. [DOI] [PubMed] [Google Scholar]
  • 48. Johe K.K., Hazel T.G., Muller T., Dugich‐Djordjevic M.M., McKay R.D., Single factors direct the differentiation of stem cells from the fetal and adult central nervous system, Genes Dev., 10: 3129–3140, 1996. [DOI] [PubMed] [Google Scholar]
  • 49. Koblar S.A., Turnley A.M., Classon B.J., Reid K.L., Ware C.B., Cheema S.S., Murphy M., Bartlett P.F., Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor, Proc. Natl. Acad. Sci. U S A, 95: 3178–3181, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Mayer M., Bhakoo K., Noble M., Ciliary neurotrophic factor and leukemia inhibitory factor promote the generation, maturation and survival of oligodendrocytes in vitro, Development, 120: 143–153, 1994. [DOI] [PubMed] [Google Scholar]
  • 51. Gard A.L., Williams W.C., 2nd Burrell M.R., Oligodendroblasts distinguished from O‐2A glial progenitors by surface phenotype (O4+GalC‐) and response to cytokines using signal transducer LIFR beta, Dev. Biol., 167: 596–608, 1995. [DOI] [PubMed] [Google Scholar]
  • 52. Marmur R., Kessler J.A., Zhu G., Gokhan S., Mehler M.F., Differentiation of oligodendroglial progenitors derived from cortical multipotent cells requires extrinsic signals including activation of gp130/LIFbeta receptors, J. Neurosci., 18: 9800–9811, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Gage F.H., Kempermann G., Palmer T.D., Peterson D.A., Ray J., Multipotent progenitor cells in the adult dentate gyrus, J. Neurobiol., 36: 249–266, 1998. [DOI] [PubMed] [Google Scholar]
  • 54. Garcia‐Verdugo J.M., Doetsch F., Wichterle H., Lim D.A., Alvarez‐Buylla A., Architecture and cell types of the adult subventricular zone: in search of the stem cells, J. Neurobiol., 36: 234–248, 1998. [DOI] [PubMed] [Google Scholar]
  • 55. Lemaire V., Koehl M., Le Moal M., Abrous D.N., Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus, Proc. Natl. Acad. Sci. U S A, 97: 11032–11037, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Neeper S.A., Gomez‐Pinilla F., Choi J., Cotman C.W., Physical activity increases mRNA for brainderived neurotrophic factor and nerve growth factor in rat brain, Brain Res., 726: 49–56, 1996. [PubMed] [Google Scholar]
  • 57. Kempermann G., van Praag H., Gage F.H., Activity‐dependent regulation of neuronal plasticity and self repair, Prog. Brain Res., 127: 35–48, 2000. [DOI] [PubMed] [Google Scholar]
  • 58. van Praag H., Kempermann G., Gage F.H., Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus, Nat. Neurosci., 2: 266–270, 1999. [DOI] [PubMed] [Google Scholar]
  • 59. Kempermann G., Gage F.H., Experience‐dependent regulation of adult hippocampal neurogenesis: effects of long‐term stimulation and stimulus withdrawal, Hippocampus, 9: 321–332, 1999. [DOI] [PubMed] [Google Scholar]
  • 60. Young D., Lawlor P.A., Leone P., Dragunow M., During M.J., Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective, Nat. Med., 5: 448–453, 1999. [DOI] [PubMed] [Google Scholar]
  • 61. Liu J., Solway K., Messing R.O., Sharp F.R., Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils, J. Neurosci., 18: 7768–7778, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Parent J.M., Yu T.W., Leibowitz R.T., Geschwind D.H., Sloviter R.S., Lowenstein D.H., Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus, J. Neurosci., 17: 3727–3738, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Kuhn H.G., Dickinson‐Anson H., Gage F.H., Neurogenesis in the dentate gyrus of the adult rat: age‐related decrease of neuronal progenitor proliferation, J. Neurosci., 16: 2027–2033, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Montaron M.F., Petry K.G., Rodriguez J.J., Marinelli M., Aurousseau C., Rougon G., Le Moal M., Abrous D.N., Adrenalectomy increases neurogenesis but not PSA‐NCAM expression in aged dentate gyrus, Eur. J. Neurosci., 11: 1479–1485, 1999. [DOI] [PubMed] [Google Scholar]
  • 65. Haughey N.J., Liu D., Nath A., Borchard A.C., Mattson M.P., Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta‐peptide: implications for the pathogenesis of Alzheimer's disease, Neuromolecular Med., 1: 125–135, 2002. [DOI] [PubMed] [Google Scholar]
  • 66. Morgan C.D., Nordin S., Murphy C., Odor identification as an early marker for Alzheimer's disease: impact of lexical functioning and detection sensitivity, J. Clin. Exp. Neuropsychol., 17: 793–803, 1995. [DOI] [PubMed] [Google Scholar]
  • 67. Devanand D.P., Michaels‐Marston K.S., Liu X., Pelton G.H., Padilla M., Marder K., Bell K., Stern Y., Mayeux R., Olfactory deficits in patients with mild cognitive impairment predict Alzheimer's disease at follow‐up, Am. J. Psychiatry, 157: 1399–1405, 2000. [DOI] [PubMed] [Google Scholar]
  • 68. Esiri M.M., Wilcock G.K., The olfactory bulbs in Alzheimer's disease, J. Neurol. Neurosurg. Psychiatry, 47: 56–60, 1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Nakatomi H., Kuriu T., Okabe S., Yamamoto S., Hatano O., Kawahara N., Tamura A., Kirino T., Nakafuku M., Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors, Cell, 110: 429–441, 2002. [DOI] [PubMed] [Google Scholar]
  • 70. Arvidsson A., Collin T., Kirik D., Kokaia Z., Lindvall O., Neuronal replacement from endogenous precursors in the adult brain after stroke, Nat. Med., 8: 963–970, 2002. [DOI] [PubMed] [Google Scholar]
  • 71. Lie D.C., Dziewczapolski G., Willhoite A.R., Kaspar B.K., Shults C.W., Gage F.H., The adult substantia nigra contains progenitor cells with neurogenic potential, J. Neurosci., 22: 6639–6649, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Flax J.D., Aurora S., Yang C., Simonin C., Wills A.M., Billinghurst L.L., Jendoubi M., Sidman R.L., Wolfe J.H., Kim S.U., Snyder E.Y., Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes, Nat. Biotechnol., 16: 1033–1039, 1998. [DOI] [PubMed] [Google Scholar]
  • 73. Terada N., Hamazaki T., Oka M., Hoki M., Mastalerz D.M., Nakano Y., Meyer E.M., Morel L., Petersen B.E., Scott E.W., Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion, Nature, 416: 542–545, 2002. [DOI] [PubMed] [Google Scholar]
  • 74. Ying Q.L., Nichols J., Evans E.P., Smith A.G., Changing potency by spontaneous fusion, Nature, 416: 545–548, 2002. [DOI] [PubMed] [Google Scholar]
  • 75. Studer L., Tabar V., McKay R.D., Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats, Nat. Neurosci., 1: 290–295, 1998. [DOI] [PubMed] [Google Scholar]
  • 76. Kim J.H., Auerbach J.M., Rodriguez‐Gomez J.A., Velasco I., Gavin D., Lumelsky N., Lee S.H., Nguyen J., Sanchez‐Pernaute R., Bankiewicz K., McKay R., Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease, Nature, 418: 50–56, 2002. [DOI] [PubMed] [Google Scholar]
  • 77. Widner H., The Lund transplant program for Parkinson's disease and patients with MPTP‐induced parkinsonism In: Freeman T.B., Widner H., eds., Cell transplantation for neurological disorders: toward reconstruction of the human central nervous system., Humana Press, Totowa , 1998, pp. 1–17. [Google Scholar]
  • 78. Hauser R.A., Fetal nigral transplantation in Parkinson's disease: the USF pilot program (12 to 24 month evaluation) In: Freeman T.B., Widner H., eds., Cell transplantation for neurological disorders: toward reconstruction of the human central nervous system., Humana Press, Totowa , 1998, pp. 19–30. [Google Scholar]
  • 79. Freed C.R., Greene P.E., Breeze R.E., Tsai W.Y., DuMouchel W., Kao R., Dillon S., Winfield H., Culver S., Trojanowski J.Q., Eidelberg D., Fahn S., Transplantation of embryonic dopamine neurons for severe Parkinson's disease, N. Engl. J. Med., 344: 710–719, 2001. [DOI] [PubMed] [Google Scholar]
  • 80. Aboody K.S., Brown A., Rainov N.G., Bower K.A., Liu S., Yang W., Small J.E., Herrlinger U., Ourednik V., Black P.M., Breakefield X.O., Snyder E.Y., From the cover: neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas, Proc. Natl. Acad. Sci. U S A, 97: 12846–12851, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81. Park K.I., Teng Y.D., Snyder E.Y., The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue, Nat. Biotechnol., 20: 1111–1117, 2002. [DOI] [PubMed] [Google Scholar]
  • 82. Fukunaga A., Uchida K., Hara K., Kuroshima Y., Kawase T., Differentiation and angiogenesis of central nervous system stem cells implanted with mesenchyme into ischemic rat brain, Cell Transplant., 8: 435–441, 1999. [DOI] [PubMed] [Google Scholar]
  • 83. Li L., Liu F., Salmonsen R.A., Turner T.K., Litofsky N.S., Di Cristofano A., Pandolfi P.P., Jones S.N., Recht L.D., Ross A.H., PTEN in neural precursor cells: regulation of migration, apoptosis, and proliferation, Mol. Cell Neurosci., 20: 21–9, 2002. [DOI] [PubMed] [Google Scholar]
  • 84. Shihabuddin L.S., Palmer T.D., Gage F.H., The search for neural progenitor cells: prospects for the therapy of neurodegenerative disease, Mol. Med. Today, 5: 474–480, 1999. [DOI] [PubMed] [Google Scholar]
  • 85. Svendsen C.N., Caldwell M.A., Ostenfeld T., Human neural stem cells: isolation, expansion and transplantation, Brain Pathol., 9: 499–513, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86. Gould E., Gross C.G., Neurogenesis in adult mammals: some progress and problems, J. Neurosci., 22: 619–623, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87. Temple S., Stem cell plasticity ‐ building the brain of our dreams, Nat. Rev. Neurosci., 2: 513–520, 2001. [DOI] [PubMed] [Google Scholar]
  • 88. Kuhn H.G., Winkler J., Kempermann G., Thal L.J., Gage F.H., Epidermal growth factor and fibroblast growth factor‐2 have different effects on neural progenitors in the adult rat brain, J. Neurosci., 17: 5820–5829, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89. Raballo R., Rhee J., Lyn‐Cook R., Leckman J.F., Schwartz M.L., Vaccarino F.M., Basic fibroblast growth factor (Fgf2) is necessary for cell proliferation and neurogenesis in the developing cerebral cortex, J. Neurosci., 20: 5012–5023, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90. Vaccarino F.M., Schwartz M.L., Raballo R., Rhee J., Lyn‐Cook R., Fibroblast growth factor signaling regulates growth and morphogenesis at multiple steps during brain development, Curr. Top. Dev. Biol., 46: 179–200, 1999. [DOI] [PubMed] [Google Scholar]
  • 91. Gritti A., Frolichsthal‐Schoeller P., Galli R., Parati E.A., Cova L., Pagano S.F., Bjornson C.R., Vescovi A.L., Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell‐like population from the subventricular region of the adult mouse forebrain, J. Neurosci., 19: 3287–3297, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92. Tropepe V., Sibilia M., Ciruna B.G., Rossant J., Wagner E.F., van der Kooy D., Distinct neural stem cells proliferate in response to EGF and FGF in the developing mouse telencephalon, Dev. Biol., 208: 166–188, 1999. [DOI] [PubMed] [Google Scholar]
  • 93. Lee J.C., Mayer‐Proschel M., Rao M.S., Gliogenesis in the central nervous system, Glia, 30: 105–121, 2000. [DOI] [PubMed] [Google Scholar]
  • 94. Briscoe J., Ericson J., The specification of neuronal identity by graded Sonic Hedgehog signalling, Semin. Cell Dev. Biol., 10: 353–362, 1999. [DOI] [PubMed] [Google Scholar]
  • 95. Zhu G., Mehler M.F., Zhao J., Yu Yung S., Kessler J.A., Sonic hedgehog and BMP2 exert opposing actions on proliferation and differentiation of embryonic neural progenitor cells, Dev. Biol., 215: 118–129, 1999. [DOI] [PubMed] [Google Scholar]
  • 96. Sieber‐Blum M., Growth factor synergism and antagonism in early neural crest development, Biochem Cell Biol., 76: 1039–1050, 1998. [PubMed] [Google Scholar]
  • 97. Andsberg G., Kokaia Z., Bjorklund A., Lindvall O., Martinez‐Serrano A., Amelioration of ischaemia‐induced neuronal death in the rat striatum by NGF‐secreting neural stem cells, Eur. J. Neurosci., 10: 2026–2036, 1998. [DOI] [PubMed] [Google Scholar]
  • 98. Martinez‐Serrano A., Bjorklund A., Ex vivo nerve growth factor gene transfer to the basal forebrain in presymptomatic middle‐aged rats prevents the development of cholinergic neuron atrophy and cognitive impairment during aging, Proc. Natl. Acad. Sci. U S A, 95: 1858–1863, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99. Pencea V., Bingaman K.D., Freedman L.J., Luskin M.B., Neurogenesis in the subventricular zone and rostral migratory stream of the neonatal and adult primate forebrain, Exp. Neurol., 172: 1–16, 2001. [DOI] [PubMed] [Google Scholar]
  • 100. Akerud P., Canals J.M., Snyder E.Y., Arenas E., Neuroprotection through delivery of glial cell linederived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease, J. Neurosci., 21: 8108–8118, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101. Hayflick L., Human cells and aging, Sci. Am., 218: 32–37, 1968. [DOI] [PubMed] [Google Scholar]
  • 102. Kruger G.M., Morrison S.J., Brain repair by endogenous progenitors, Cell, 110: 399–402, 2002. [DOI] [PubMed] [Google Scholar]
  • 103. Harley C.B., Futcher A.B., Greider C.W., Telomeres shorten during ageing of human fibroblasts, Nature, 345: 458–460, 1990. [DOI] [PubMed] [Google Scholar]
  • 104. Bodnar A.G., Ouellette M., Frolkis M., Holt S.E., Chiu C.P., Morin G.B., Harley C.B., Shay J.W., Lichtsteiner S., Wright W.E., Extension of lifespan by introduction of telomerase into normal human cells, Science, 279: 349–352, 1998. [DOI] [PubMed] [Google Scholar]
  • 105. Allsopp R.C., Weissman I.L., Replicative senescence of hematopoietic stem cells during serial transplantation: does telomere shortening play a role?, Oncogene, 21: 3270–3273, 2002. [DOI] [PubMed] [Google Scholar]
  • 106. Greenberg R.A., Allsopp R.C., Chin L., Morin G.B., DePinho R.A., Expression of mouse telomerase reverse transcriptase during development, differentiation and proliferation, Oncogene, 16: 1723–1730, 1998. [DOI] [PubMed] [Google Scholar]
  • 107. Martin‐Rivera L., Herrera E., Albar J.P., Blasco M.A., Expression of mouse telomerase catalytic subunit in embryos and adult tissues, Proc. Natl. Acad. Sci. U S A, 95: 10471–10476, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108. Prowse K.R., Greider C.W., Developmental and tissue‐specific regulation of mouse telomerase and telomere length, Proc. Natl. Acad. Sci. U S A, 92: 4818–4822, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 109. Blasco M.A., Funk W., Villeponteau B., Greider C.W., Functional characterization and developmental regulation of mouse telomerase RNA, Science, 269: 1267–1270, 1995. [DOI] [PubMed] [Google Scholar]
  • 110. Haik S., Gauthier L.R., Granotier C., Peyrin J.M., Lages C.S., Dormont D., Boussin F.D., Fibroblast growth factor 2 up regulates telomerase activity in neural precursor cells, Oncogene, 19: 2957–2966, 2000. [DOI] [PubMed] [Google Scholar]
  • 111. Vaziri H., Dragowska W., Allsopp R.C., Thomas T.E., Harley C.B., Lansdorp P.M., Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age, Proc. Natl. Acad. Sci. U S A, 91: 9857–9860, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 112. Lindsey J., McGill N.I., Lindsey L.A., Green D.K., Cooke H.J., In vivo loss of telomeric repeats with age in humans, Mutat. Res., 256: 45–48, 1991. [DOI] [PubMed] [Google Scholar]
  • 113. Wyllie F.S., Jones C.J., Skinner J.W., Haughton M.F., Wallis C., Wynford‐Thomas D., Faragher R.G., Kipling D., Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts, Nat. Genet., 24: 16–17, 2000. [DOI] [PubMed] [Google Scholar]
  • 114. Faragher R.G., Kipling D., How might replicative senescence contribute to human ageing?, Bioessays, 20: 985–991, 1998. [DOI] [PubMed] [Google Scholar]
  • 115. Campisi J., Cancer, aging and cellular senescence, In Vivo. 14: 183–188, 2000. [PubMed] [Google Scholar]
  • 116. Goldstein S., Replicative senescence: the human fibroblast comes of age, Science, 249: 1129–1133, 1990. [DOI] [PubMed] [Google Scholar]
  • 117. Lee H.W., Blasco M.A., Gottlieb G.J., Horner J.W., 2nd , Greider C.W., DePinho R.A., Essential role of mouse telomerase in highly proliferative organs, Nature, 392: 569–574, 1998. [DOI] [PubMed] [Google Scholar]
  • 118. Rudolph K.L., Chang S., Lee H.W., Blasco M., Gottlieb G.J., Greider C., DePinho R.A., Longevity, stress response, and cancer in aging telomerase‐deficient mice, Cell, 96: 701–712, 1999. [DOI] [PubMed] [Google Scholar]
  • 119. Oikawa S., Tada‐Oikawa S., Kawanishi S., Sitespecific DNA damage at the GGG sequence by UVA involves acceleration of telomere shortening, Biochemistry, 40: 4763–4768, 2001. [DOI] [PubMed] [Google Scholar]
  • 120. Petersen S., Saretzki G., von Zglinicki T., Preferential accumulation of single‐stranded regions in telomeres of human fibroblasts, Exp. Cell Res., 239: 152–160, 1998. [DOI] [PubMed] [Google Scholar]
  • 121. Henle E.S., Han Z., Tang N., Rai P., Luo Y., Linn S., Sequence‐specific DNA cleavage by Fe2+‐ mediated fenton reactions has possible biological implications, J. Biol. Chem., 274: 962–971, 1999. [DOI] [PubMed] [Google Scholar]
  • 122. Sitte N., Merker K., Von Zglinicki T., Grune T., Davies K.J., Protein oxidation and degradation during cellular senescence of human BJ fibroblasts: part I–effects of proliferative senescence, Faseb J., 14: 2495–2502, 2000. [DOI] [PubMed] [Google Scholar]
  • 123. von Zglinicki T., Pilger R., Sitte N., Accumulation of single‐strand breaks is the major cause of telomere shortening in human fibroblasts, Free Radic. Biol. Med., 28: 64–74, 2000. [DOI] [PubMed] [Google Scholar]
  • 124. Samani N.J., Boultby R., Butler R., Thompson J.R., Goodall A.H., Telomere shortening in atherosclerosis, Lancet, 358: 472–473, 2001. [DOI] [PubMed] [Google Scholar]
  • 125. von Zglinicki T., Oxidative stress shortens telomeres, Trends Biochem. Sci., 27: 339–344, 2002. [DOI] [PubMed] [Google Scholar]
  • 126. Bryan T.M., Englezou A., Dalla‐Pozza L., Dunham M.A., Reddel R.R., Evidence for an alternative mechanism for maintaining telomere length in human tumors and tumor‐derived cell lines, Nat. Med., 3: 1271–1274, 1997. [DOI] [PubMed] [Google Scholar]
  • 127. Shay J.W., Gazdar A.F., Telomerase in the early detection of cancer, J. Clin. Pathol., 50: 106–109, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 128. Bryan T.M., Englezou A., Gupta J., Bacchetti S., Reddel R.R., Telomere elongation in immortal human cells without detectable telomerase activity, EMBO J., 14: 4240–4248, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 129. Gobbel G.T., Bellinzona M., Vogt A.R., Gupta N., Fike J.R., Chan P.H., Response of postmitotic neurons to X‐irradiation: implications for the role of DNA damage in neuronal apoptosis, J. Neurosci., 18: 147–155, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 130. Yoshikawa K., Cell cycle regulators in neural stem cells and postmitotic neurons, Neurosci. Res., 37: 1–14, 2000. [DOI] [PubMed] [Google Scholar]
  • 131. Edgar B., Diversification of cell cycle controls in developing embryos, Curr. Opin. Cell Biol., 7: 815–824, 1995. [DOI] [PubMed] [Google Scholar]
  • 132. Callaghan D.A., Dong L., Callaghan S.M., Hou Y.X., Dagnino L., Slack R.S., Neural precursor cells differentiating in the absence of Rb exhibit delayed terminal mitosis and deregulated E2F 1 and 3 activity, Dev. Biol., 207: 257–270, 1999. [DOI] [PubMed] [Google Scholar]
  • 133. Weinberg R.A., The retinoblastoma protein and cell cycle control, Cell, 81: 323–330, 1995. [DOI] [PubMed] [Google Scholar]
  • 134. Lois A.F., Cooper L.T., Geng Y., Nobori T., Carson D., Expression of the p16 and p15 cyclin‐dependent kinase inhibitors in lymphocyte activation and neuronal differentiation, Cancer Res., 55: 4010–4013, 1995. [PubMed] [Google Scholar]
  • 135. Park D.S., Morris E.J., Padmanabhan J., Shelanski M.L., Geller H.M., Greene L.A., Cyclin‐dependent kinases participate in death of neurons evoked by DNA‐damaging agents, J. Cell Biol., 143: 457–467, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 136. Arendt T., Alzheimer's disease as a loss of differentiation control in a subset of neurons that retain immature features in the adult brain, Neurobiol. Aging, 21: 783–796, 2000. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES