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Neural stem cell therapy for neuropsychiatric disorders

  • Michael Valenzuela (a1) (a2), Kuldip Sidhu (a3), Sophia Dean (a1) (a3) and Perminder Sachdev (a1) (a2)
<span class='bold'>Objective:</span>

To conduct a comprehensive literature review of the area of neural stem cells and neuropsychiatry.

<span class='bold'>Methods:</span>

‘Neural stem cells’ (NSCs) and ‘neurogenesis’ were used as keywords in Medline (1966 – November 2006) to identify relevant papers in the areas of Alzheimer’s disease (AD), depression, schizophrenia and Parkinson’s disease (PD). This list was supplemented with papers from reference lists of seminal reviews.

<span class='bold'>Results:</span>

The concept of a ‘stem cell’ continues to evolve and is currently defined by operational criteria related to symmetrical renewal, multipotency and functional viability. In vivo adult mammalian neurogenesis occurs in discrete niches in the subventricular and subgranular zones – however, functional precursor cells can be generated in vitro from a wide variety of biological sources. Both artificial and physiological microenvironment is therefore critical to the characteristics and behaviour of neural precursors, and it is not straightforward how results from the laboratory can be extrapolated to the living organism. Transplant strategies in PD have shown that it is possible for primitive neural tissue to engraft into neuropathic brain areas, become biologically functional and lead to amelioration of clinical signs and symptoms. However, with long-term follow-up, significant problems related to intractable side-effects and potential neoplastic growth have been reported. These are therefore the potentials and pitfalls for NSC technology in neuropsychiatry. In AD, the physiology of amyloid precursor protein may directly interact with NSCs, and a role in memory function has been speculated. The role of endogenous neurogenesis has also been implicated in the etiology of depression. The significance of NSCs and neurogenesis for schizophrenia is still emerging.

<span class='bold'>Conclusions:</span>

There are a number of technical and conceptual challenges ahead before the promise of NSCs can be harnessed for the understanding and treatment of neuropsychiatric disorders. Further research into fundamental NSC biology and how this interacts with the neuropsychiatric disease processes is required.

Corresponding author
Michael Valenzuela, BSc (Psychol) Hons, MBBS Hons, PhD Neuropsychiatric Institute, The Prince of Wales Hospital, Sydney, NSW 2031, Australia. Tel: 61 2 9382 2712; Fax: 61 2 9382 3774; E-mail:
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1.Kempermann G. Adult neurogenesis. New York: Oxford University Press, 2006.
2.Singec I, Knoth R, Meyer R et al. Defining the actual sensitivity and specificity of the neurosphere assay in stem cell biology. Nat Methods 2006;3:801806.
3.Reynolds B, Rietze R. Neural stem cells and neurospheres – re-evaluating the relationship. Nat Methods 2005;2:333336.
4.Wilson S, Edlund T. Neural induction: toward a unifying mechanism. Nat Neurosci 2001; 4 Suppl:1161–1168.
5.Munoz-Sanjuan I, Brivanlou A. Neural induction, the default model and embryonic stem cells. Nat Rev Neurosci 2002;3:271280.
6.Lim U, Sidhu K, Tuch B. Derivation of motor neurons from three clonal human embryonic stem cell lines. Curr Neurovasc Res 2006;3:281288.
7.Hockfield S, McKay R. Identification of major cell classes in the developing mammalian nervous system. J Neurosci 1985;5:33103328.
8.Rutishauser U, Acheson A, Hall A, Mann D, Sunshine J. The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions. Science 1988;240:5357.
9.Uchida N, Buck D, He D et al. Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci U S A 2000;97:1472014725.
10.Garcia A, Doan N, Imura T, Bush T, Sofroniew M. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat Neurosci 2004;7:12331241.
11.McNay D, Pelling M, Claxton S, Guillemot F, Ang S. Mash1 is required for generic and subtype differentiation of hypothalamic neuroendocrine cells. Mol Endocrinol 2006;20:16231632.
12.Bylund M, Andersson E, Novitch B, Muhr J. Vertebrate neurogenesis is counteracted by Sox1-3 activity. Nat Neurosci 2003;6:11621168.
13.Brazel C, Limke T, Osborne J et al. Sox2 expression defines a heterogenous population of neurosphere-forming cells in the adult murine brain. Aging Cell 2005;4:197207.
14.Reimers D, Lopez-Toledano M, Mason I et al. Developmental expression of fibroblast growth factor (FGF) receptors in neural stem cell progeny. Modulation of neuronal and glial lineages by basic FGF treatment. Neurol Res 2001;23:612621.
15.Buffo A, Vosko M, Ertuck D et al. Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. Proc Natl Acad Sci U S A 2005;102:1818318188.
16.Fanarraga M, Avila J, Zabala J. Expression of unphosphorylated class III beta-tubulin isotype in neuroepithelial cells demonstrates neuroblast commitment and differentiation. Eur J Neurosci 1999;11:517527.
17.Dupree J, Popko B. Genetic dissection of myelin galactolipid function. Neurocytology 1999;28:271279.
18.Binder L, Frankfurter A, Rebhun L. Differential localization of MAP-2 and tau in mammalian neurons in situ. Proc Natl Acad Sci U S A 1986;466:145166.
19.Mullen R, Buck C, Smith A. NeuN, a neuronal specific nuclear protein in vertebrates. Development 1992;116:201.
20.Pickel V. Immunocytochemical localization of neuronal antigens: tyrosine hydroxylase, substance P, [Met5]-enkephalin. Fed Proc 1979;38:23742380.
21.Wiedenmann B, Franke W. Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles. Cell 1985;41:10171028.
22.Kempermann G, Gast D, Gage FH. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment [see Comments]. Ann Neurol 2002;52:135143.
23.Eriksson P, Bjork-Eriksson T, Alborn A, Nordborg C, Peterson D, Gage F. Neurogenesis in the adult human hippocampus. Nat Med 1998;4:13131317.
24.Kuhn H, Dickinson-Anson H, Gage F. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 1996;16:20272033.
25.Altman J, Das G. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965;124:319335.
26.Ming G, Song H. Adult neurogenesis in the mammalian central nervous system. Ann Rev Neurosci 2005;28:223250.
27.Shors T, Miesegaes G, Beylin A et al. Neurogenesis in the adult is involved in the formation of trace memories. Nature 2001;410:372376.
28.Meshi S, Drew M, Saxe M et al. Hippocampal neurogenesis is not required for behavioural effects of environmental enrichment. Nat Neurosci 2006;9:729731.
29.Reynolds B, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992;255:17071710.
30.Gottlieb D. Large scale sources of neural stem cells. Ann Rev Neurosci 2002;25:381407.
31.Bez A, Corsini E, Curti D et al. Neurosphere and neurosphere-forming cells: morphological and ultrastructural characterization. Brain Res 2003;993:1829.
32.Seaberg R, Van der Kooy D. Stem and progenitor cells: the premature desertion of rigorous definitions. Trends Neurosci 2003;26:125131.
33.Nagato M, Heike T, Kato T et al. Prospective characterisation of neural stem cells by flow cytometry analysis using a combination of surface markers. J Neurosci Res 2005;80:456466.
34.Cattaneo E, McKay R. Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature 1990;347:762765.
35.Conti L, Pollard S, Gorba T et al. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol 2005;3:e283.
36.Pollard S, Conti L, Sun Y, Goffredo D, Smith A. Adherent neural stem (NS) cells from foetal and adult forebrain. Cereb Cortex 2006;16:i112i120.
37.Ostenfield T, Caldwell M, Prowse K, Linskens M, Jauniaux E, Svendsen C. Human neural precursor cells express low levels of telomerase in vitro and show diminishing cell proliferation with extensive axonal outgrowth following transplantation. Exp Neurol 2000;164:226.
38.Thomson J, Marshall V, Trojanowski J. Neural differentiation of rhesus embryonic stem cells. Apmis 1998;106:149157.
39.Bain G, Ray W, Yao M, Gottlieb D. Retinoic acid promotes neural and represses mesodermal gene expression in mouse embryonic stem cells in culture. Biochem Biophys Res Commun 1996;223:691694.
40.Suda Y, Suzuki M, Ikawa Y, Aizawa S. Mouse embryonic stem cells exhibit indefinite proliferative potential. J Cell Physiol 1987;133:197201.
41.Qu T, Brannen H, Kim H, Sugaya K. Human neural stem cells improve cognitive functions of aged brain. Neuroreport 2001;12:11271132.
42.Freed C, Greene P, Breeze R et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s Disease. New Engl J Med 2001;344:710719.
43.Muotri A, Nakashima K, Toni N, Sandler V, Gage F. Development of functional human embryonic stem cell-derived neurons in mouse brain. Proc Natl Acad Sci U S A 2005;102:1864418648.
44.Roy N, Cleren C, Singh S, Yang L, Beal M, Goldman S. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with teleromase-immortalised midbrain astrocytes. Nat Med 2006;2:12591268.
45.Palmer T, Markakis E, Willhoite A, Safar F, Gage F. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci 1999;19:84878497.
46.Kozorovitskiy Y, Gould E. Stem cell fusion in the brain. Nat Cell Biol 2003;5:952954.
47.Jiang Y, Jahagirdar B, Reinhardt R et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:4149.
48.Toma J, Akhavan M, Fernandes K et al. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol 2001;3:778784.
49.Fernandes K, McKenzie I, Mill P et al. A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol 2004;6:10821093.
50.Joannides A, Gaughwin P, Schwiening C, Majed H, Compston A, Chandran S. Efficient generation of neural precursors from adult human skin: astrocytes promote neurogenesis from skin-derived stem cells. Lancet 2004;364:172178.
51.Rossi F, Cattaneo E. Neural stem cell therapy for neurological diseases: dreams and reality. Nat Rev Neurosci 2002;3:401409.
52.van Praag H, Christie B, Sejnowski T, Gage F. Running enhances neurogenesis, learning and long-term potentiations in mice. Proc Natl Acad Sci U S A 1999;96:1342713431.
53.Ickes B, Pham T, Sanders L, Albeck D, Mohammed A, Granholm A. Long-term environmental enrichment leads to regional increases in neurotrophin levels in rat brain. Exp Neurol 2000;164:4552.
54.Aboody K, Brown A, Rainov N et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 2000;97:1284612851.
55.Pearson H, Peers C. Physiological roles for amyloid b peptides. J Physiol 2006;575:510.
56.Hayashi M, Kashiwagi S, Ohta H, Nakajima M, Kawashima T, Yoshikawa K. Alzheimer’s amyloid protein precursor enhances proliferation of neural stem cells from fetal rat brain. Biochem Biophys Res Commun 1994;205:936943.
57.Nithianantharajah J, Hannan A. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci 2006;7:697709.
58.Gould E, Tanapat P, McEwen B, Flugge G, Fuchs E. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress. Proc Natl Acad Sci U S A 1998;95:31683171.
59.Jin K, Zhu Y, Sun Y, Mao X, Xie L, Greenberg D. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A 2002;99:1194611950.
60.Pencea V, Bingaman K, Wiegand S, Luskin M. 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 2001;21:67066717.
61.Kotzbauer P, Holtzman D. Expectations and challenges in the therapeutic use of neurotrophic factors. Ann Neurol 2006;59:444447.
62.Lin L, Doherty D, Lile J et al. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 1993;260:11301132.
63.Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239259.
64.Kril J, Patel S, Harding A, Halliday GM. Neuron loss from the hippocampus of Alzheimer’s disease exceeds extracellular neurofibrillary tangle formation. Acta Neuropathol 2002;103:370376.
65.DeKosky S, Scheff S. Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 1990;27:457464.
66.Terry RD, Masliah E, Salmon DP et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572580.
67.Grady C, McIntosh A, Beig S, Keightley M, Burian H, Black S. Evidence from functional neuroimaging of a compensatory prefrontal network in Alzheimer’s disease. J Neurosci 2003;23:986993.
68.Valenzuela M, Sachdev P. Brain reserve and dementia: a systematic review. Psychol Med 2006;36:441454.
69.Kwak Y, Brannen C, Qu T et al. Amyloid precursor protein regulates differentiation of human neural stem cells. Stem Cells Dev 2006;15:381389.
70.Haughey J, Nath A, Chan S, Borchard A, Rao M, Mattson M. Disruption of neurogenesis by amyloid b-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer’s disease. J Neurochem 2002;83:15091524.
71.Jin K, Peel A, Xiao OM et al. Increased hippocampal neurogenesis in Alzheimer’s disease. Proc Natl Acad Sci U S A 2004;101:343347.
72.Wang Q, Matsumoto Y, Shindo T et al. Neural stem cells transplantation in cortex in a mouse model of Alzheimer’s disease. J Med Invest 2006;53:6169.
73.Tuszynski M, Thal L, Pay M et al. A phase I clinical trial of nerve growth factor gene therapy for Alzheimer’s disease. Nat Med 2005;11:551555.
74.Alzheimer Research Forum. Alzforum. (accessed January 1, 2006).
75.De Rosa R, Garcia A, Braschi C et al. Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice. Proc Natl Acad Sci U S A 2005;102:38113816.
76.Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attentuates Alzheimer disease-like pathology in the PDAPP mouse. Nature 1999;400:173177.
77.Scheff S, Price DA. Synaptic pathology in Alzheimer’s disease: a review of ultrastructural studies. Neurobiol Aging 2003;24:10291046.
78.Robinson S, Bishop G. Ab as a bioflocculant: implications for the amyloid hypothesis of Alzheimers disease. Neurobiol Aging 2002;23:10511072.
79.Sapolsky R. Stress, the aging brain and the mechanisms of neuron death. Cambridge: MIT Press, 1992.
80.Jacobs B, Van Praag H, Gage F. Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry 2000;5:262269.
81.Duman R, Heninger G, Nestler E. A molecular and cellular theory of depression. Am J Psychiatry 1997;54:597606.
82.Gould E, McEwen B, Tanapat P, Galea L, Fuchs E. Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci 1997;17:24922498.
83.Gould E, Cameron H, Daniels D, Wooley C, McEwen B. Adrenal hormones suppress cell division in the adult dentate gyrus. J Neurosci 1992;12:36423650.
84.Moghaddam B, Bolinao M, Stein-Behrens B, Sapolsky R. Glucocorticoids mediate the stress-induced extracellular accumulation of glutamate. Brain Research 1994;655:251254.
85.Fanburg B, Lee S. A new role for an old molecule: serotonin as a mitogen. Am J Physiol 1997;16:L795L806.
86.Malberg J, Eisch A, Nestler E, Duman R. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 2000;20:91049110.
87.Malberg J, Duman R. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 2003;28:15621571.
88.Radley J, Jacobs B. 5-HT1A receptor antagonist administration decreases cell proliferation in the dentate gyrus. Brain Res 2002;995:264267.
89.Santarelli L, Saxe M, Gross C et al. Requirement of hippocampal neurogenesis for the behavioural effects of antidepressants. Science 2003;301:805809.
90.Madsen T, Treschow A, Bengzon J, Bolwig T, Wortwein G. Increased neurogenesis in a model of electroconvulsive therapy. Neuroscience 2000;119:635642.
91.Shirayama Y, Chen A, Nakagawa S, Russell D, Duman R. Brain-derived neurotrophic factor produces antidepressant effects in behavioural models of depression. J Neurosci 2002;22:32513261.
92.Reif A, Finger M, Strobel A, Lauer M, Schmitt A, Lesch K. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 2006;11:514522.
93.Hilborn R. Sea gulls, butterflies, and grasshoppers: a brief history of the butterfly effect in nonlinear dynamics. Am J Physics 2004;72:425427.
94.Casti J. Complexification: explaining a paradoxical world through the science of surprise. New York: Harper Collins, 1994.
95.Heckers S, Konradi C. Hippocampal neurons in schizophrenia. J Neural Transm 2002;109:891905.
96.Guidotti A, Auta J, Davis J et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder. Arch Gen Psychiatry 2000;57:10611069.
97.Kim H, Qu T, Lacor V et al. Reelin function in neural stem cell biology. Proc Natl Acad Sci U S A 2002;99:40204025.
98.Becker A, Peters B, Schroeder H et al. Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Prog NeuroPsychopharmaco Biol Psychiatry 2003;27:687700.
99.Kippin T, Kapur S, Can der Kooy D. Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. J Neurosci 2005;25:58155823.
100.Lindvall O, Brundin P, Widner H et al. Grafts of fetal dopamine neurons survive and improve motor function in Parksinson’s disease. Science 1990;247:574577.
101.Harrower T, Tyers P, Hooks Y, Barker R. Long-term survival and integration of porcine expanded neural precursor cell grafts in a rat model of Parkinson’s disease. Exp Neurol 2006;197:5669.
102.Takagi Y, Takahashi J, Saiki H et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J Clin Invest 2005;115:102109.
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