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. 2006 Apr 5;9(3):499–513. doi: 10.1111/j.1750-3639.1999.tb00538.x

Human Neural Stem Cells: Isolation, Expansion and Transplantation

Clive N Svendsen 1,✉, Maeve A Caldwell 1, Thor Ostenfeld 1
PMCID: PMC8098156  PMID: 10416990

Abstract

Neural stem cells, with the capacity to self renew and produce the major cell types of the brain, exist in the developing and adult rodent central nervous system (CNS). Their exact function and distribution is currently being assessed, but they represent an interesting cell population, which may be used to study factors important for the differentiation of neurons, astrocytes and oligodendrocytes. Recent evidence suggests that neural stem cells may also exist in both the developing and adult human CNS. These cells can be grown in vitro for long periods of time while retaining the potential to differentiate into nervous tissue. Significantly, many neurons can be produced from a limited number of starting cells, raising the possibility of cell replacement therapy for a wide range of neurological disorders. This review summarises this fascinating and growing field of neurobiology, with a particular focus on human tissues.

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References

  • 1. Alvarez‐Buylla A, Temple S (1998) Stem cells in the developing and adult nervous system. J Neurobiol. 36: 105–110. [PubMed] [Google Scholar]
  • 2. Arsenijevic Y, Weiss S (1998) Insulin‐like growth factor‐I is a differentiation factor for postmitotic CNS stem cell‐derived neuronal precursors: Distinct actions from those of brain‐derived neurotrophic factor. J Neurosci 18: 2118–2128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Avellana‐Adalid V, Nait‐Oumesmar B, Lachapelle F, Baron‐Van EA (1996) Expansion of rat oligodendrocyte progenitors into proliferative “oligospheres” that retain differentiation potential. J Neurosci Res. 45: 558–570. [DOI] [PubMed] [Google Scholar]
  • 4. Bjorklund A, Svendsen CN (1999) Breaking the brain blood barrier. Nature 397: 569–570. [DOI] [PubMed] [Google Scholar]
  • 5. Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL (1999) Turning brain into blood: A hematopoietic fate adopted by adult neural stem cells in vivo . Science 283: 534–537. [DOI] [PubMed] [Google Scholar]
  • 6. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu C, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE (1998) Extension of life‐span by introduction of telomerase into normal human cells. Science 279: 349–352. [DOI] [PubMed] [Google Scholar]
  • 7. Bouvier MM, Mytilineou C (1995) Basic fibroblast growth factor increases division and delays differentiation of dopamine precursors in vitro. J Neurosci 15: 7141–7149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Brustle O, Choudhary K, Karram K, Huttner A, Murray K, Dubois‐Dalcq M, McKay RDG (1998) Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats. Nat Biotechnol 16: 1040–1044. [DOI] [PubMed] [Google Scholar]
  • 9. Buc‐Caron M (1995) Neuroepithelial progenitor cells expanted from human fetal brain proliferate and differentiate in vitro. Neurobiology of Disease 12: 37–47. [DOI] [PubMed] [Google Scholar]
  • 10. Caldwell MA, Svendsen CN (1998) Heparin, but not other proteoglycans potentiates the mitogenic effects of FGF‐2 on mesencephalic precursor cells. Exp Neurol. 152: 1–10. [DOI] [PubMed] [Google Scholar]
  • 11. Cameron HA, Hazel TG, McKay RDG (1998) Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol 36: 287–306. [PubMed] [Google Scholar]
  • 12. Campbell K, Olsson M, Björklund A (1995) Regional incorporation and site‐specific differentaition of striatal precursors transplanted to the embryonic forebrain ventricle. Neuron 15: 1259–1273. [DOI] [PubMed] [Google Scholar]
  • 13. Carpenter MK, Cui X, Hu Z‐Y, Jackson J, Sherman S, Seiger A, Whalberg L (1999) In vitro expansion of a multipotent population of human neural progenitor cells. Exp Neurol In Press. [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 fetal brain. Neurosci 76: 1121–1128. [DOI] [PubMed] [Google Scholar]
  • 15. Chenn A, McConnell SK (1995) Cleavage orientation and the asymmetric inheritance of Notch 1 immunoreactivity in mammalian neurogenesis. Cell 82: 631–641. [DOI] [PubMed] [Google Scholar]
  • 16. Cunha GR, Vanderslice KD (1984) Identification of histological sections of species origin of cells from mouse, rat and human. Stain Technology 59: 7–12. [DOI] [PubMed] [Google Scholar]
  • 17. Davis AA, Temple S (1994) A self‐renewing multipotential stem cell in embryonic rat cerebral cortex. Nature 372: 263–266. [DOI] [PubMed] [Google Scholar]
  • 18. Doe CQ, Fuerstenberg S, Peng CY (1998) Neural stem cells: from fly to vertebrates. J Neurobiol 36: 111–127. [PubMed] [Google Scholar]
  • 19. Eriksson PS, Perfilieva E, Bjork‐Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4: 1313–1317. [DOI] [PubMed] [Google Scholar]
  • 20. Fishell G (1995) Striatal precursors adopt cortical identities in response to local cues. Development 121: 803–812. [DOI] [PubMed] [Google Scholar]
  • 21. Flax JD, Aurora S, Yang C, Simonin C, Wills AM, Billinghurst LL, Jendoubi M, 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 Biotechnol 16: 1033–1039. [DOI] [PubMed] [Google Scholar]
  • 22. Gage FH (1998) Cell Therapy. Nature 392 (supplement): 18–24. [PubMed] [Google Scholar]
  • 23. Gage FH, Ray J, Fisher LJ (1995) Isolation, characterisation, and use of stem cells from the CNS. In Annual Reviews of Neuroscience . Eds. Cowan, W.M. ; Shooter, E.M. ; Stevens, C.F. ; Thompson, R.F. 159–192. [DOI] [PubMed]
  • 24. Gaiano N, Fishell G (1998) Transplantation as a tool to study progenitors within the vertebrate nervous system. J Neurobiol 36: 152–161. [PubMed] [Google Scholar]
  • 25. Gensburger C, Labourdette G, Sensenbrenner, M (1987) Brain basic fibroblast growth factor stimulates the proliferation of rat neuronal precursor cells in vitro. FEBS Lett 217: 1–5. [DOI] [PubMed] [Google Scholar]
  • 26. 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]
  • 27. Goldman SA (1998) Adult neurogenesis: from canaries to the clinic. J Neurobiol 36: 267–286. [PubMed] [Google Scholar]
  • 28. Gritti A, Parati EA, Cova L, Frolichsthal P, Galli P, Wanke E, Faravelli L, Morassutti D, 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]
  • 29. Hall PA, Watt FM (1989) Stem cells: the generation and maintenance of cellular diversity. Development 106: 619–633. [DOI] [PubMed] [Google Scholar]
  • 30. Hammang JP, Archer DR, Duncan ID (1997) Myelination following transplantation of EGF‐responsive neural stem cells into a myelin‐deficient environment. Exp Neurol 147: 84–95. [DOI] [PubMed] [Google Scholar]
  • 31. Harrison RG (1907) Observations on the living developing nerve fiber. J Exp Zoology 9: 787–846. [Google Scholar]
  • 32. Hayflick L (1997) Mortality and immortality at the cellular level. A review. Biochemistry (Mosc.) 62: 1180–1190. [PubMed] [Google Scholar]
  • 33. Jacobson M (1991) The germinal cell, histiogenesis, and lineages of nerve cells In: Developmental Neurobiology Jacobson M, Plenum Press. [Google Scholar]
  • 34. Jan YN, Jan LY (1995) Maggot's hair and bug's eye: role of cell interactions and intrinsic factors in cell fate specification. Neuron 14: 1–5. [DOI] [PubMed] [Google Scholar]
  • 35. Joh K, Hazel T, Muller T, Dugich‐Djordjevic M, McKay RDG (1996) Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes and Development 10: 3129–3140. [DOI] [PubMed] [Google Scholar]
  • 36. Johansson CB, Momma S, Clarke DL, Risling M, Lendahl, U , Frisén J (1999) Identification of a neural stem cell in the adult mammalian central nervous system. Cell 96: 25–34. [DOI] [PubMed] [Google Scholar]
  • 37. Kilpatric TJ, Bartlett PF (1995) Cloned multipotential precursors from the mouse cerebrum require FGF‐2, wheras glial restricted precursors are stimulated with either FGF‐2 or EGF. J Neurosci 15: 3653–3661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Kilpatrick TJ, Richards LJ, Bartlett PF (1995) The regulation of neural precursor cells within the mammalian brain. Mol Cell Neurosci 6: 2–15. [DOI] [PubMed] [Google Scholar]
  • 39. Kirschenbaum B, Nedergaard M, Preuss A, Barami K, Fraser RAR, Goldman SA (1994) In vitro neuronal production and differentiation by precursor cells derived from the adult human forebrain. Cerbral Cortex 4: 476–589. [DOI] [PubMed] [Google Scholar]
  • 40. 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]
  • 41. Lillien L (1998) Neural progenitors and stem cells: mechanisms of progenitor heterogeneity. Curr Opin Neurobiol 8: 37–44. [DOI] [PubMed] [Google Scholar]
  • 42. Ling ZD, Potter ED, Lipton JW, Carvey PM (1998) Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines. Exp Neurol 149: 411–423. [DOI] [PubMed] [Google Scholar]
  • 43. Mayer‐Proschel M, Kalyani AJ, Mujtaba T, Rao, MS (1997) Isolation of lineage‐restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron 19: 773–785. [DOI] [PubMed] [Google Scholar]
  • 44. McKay RDG (1997) Stem cells in the central nervous system. Science 276: 66–71. [DOI] [PubMed] [Google Scholar]
  • 45. Menezes JRL, Luskin MB (1994) Expression of neuron‐specific tubulin defines a novel population in the profliferative layers of the developing telencephalon. J Neurosci 14: 5399–5416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46. Morrison SJ, Shah NM, Anderson DJ (1997) Regulatory mechanisms in stem cell biology. Cell 88: 287–298. [DOI] [PubMed] [Google Scholar]
  • 47. Mujtaba T, Mayer‐Proschel M, Rao MS (1998) A common neural progenitor for the CNS and PNS. Dev Biol 200: 1–15. [DOI] [PubMed] [Google Scholar]
  • 48. Murray K, Dubois‐Dalcq M (1997) Emergence of oligodendrocytes from human neural spheres. J Neurosci Res 50: 146–156. [DOI] [PubMed] [Google Scholar]
  • 49. 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]
  • 50. Palmer TD, Takahashi J, Gage FH (1997) The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci 8: 389–404. [DOI] [PubMed] [Google Scholar]
  • 51. Patterson PH (1994) Leukemia inhibitory factor, a cytokine at the interface between neurobiology and immunology. PNAS 91: 7833–7835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Pincus DW, Keyoung HM, Harrison‐Restelli C, Goodman RR, Fraser RA, Edgar M, Sakakibara S, Okano H, Nedergaard M, Goldman SA (1998) Fibroblast growth factor‐2/brain‐derived neurotrophic factor‐associated maturation of new neurons generated from adult human subependymal cells. Ann Neurol 43: 576–585. [DOI] [PubMed] [Google Scholar]
  • 53. Ponten J, Stein WD, Shall S (1983) A quantitiative analysis of the aging of human glial cells in culture. J Cell Physio 117: 342–352. [DOI] [PubMed] [Google Scholar]
  • 54. Potten CS, Loeffler M (1990) Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110: 1001–1020. [DOI] [PubMed] [Google Scholar]
  • 55. Price J, Turner D, Cepko C (1987) Lineage analysis in the vertebrate nervous system by retrovirus‐mediated gene transfer. Proc Natl Acad Sci USA 84: 156–160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Raff MC, Abney ER, Fok‐Seang J (1985) Reconstitution of a developmental clock in vitro: a critical role for astrocytes in the timing of oligodendrocyte differentiation. Cell 42: 61–69. [DOI] [PubMed] [Google Scholar]
  • 57. Raff MC, Miller RH, Noble M (1983) A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on the culture medium. Nature 303: 390–396. [DOI] [PubMed] [Google Scholar]
  • 58. Ramon Y Cajal S (1890) Sur l'origine et les ramifications des fibres nerveuses de la moelle embryonaire. Anat Ang 5: 609–613. [Google Scholar]
  • 59. Ray J, Peterson DA, Schinstine M, Gage FH (1993) Proliferation, differentiation, and long‐term culture of primary hippocampal neurons. Proc Natl Acad Sci USA 90: 3602–3606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60. Reynolds BA, 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]
  • 61. 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]
  • 62. Reynolds BA, Weiss S (1996) Clonal and population analyses demonstrate that an EGF‐responsive mammalian embryonic CNS precursor is a stem cell. Develop Biol 175: 1–13. [DOI] [PubMed] [Google Scholar]
  • 63. Richards LJ, Kilpatric TJ, Bartlett PF (1992) De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci USA 89: 8591–8595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Richards LJ, Kilpatrick TJ, Dutton R, Tan SS, Gearing DP, Bartlett PF, Murphy M (1996) Leukaemia inhibitory factor or related factors promote the differentiation of neuronal and astrocytic precursors within the developing murine spinal cord. Eur J Neurosci 8: 291–299. [DOI] [PubMed] [Google Scholar]
  • 65. Sabate O, Horellou P, Vigne E, Colin P, Perricaudet M, Buc‐Caron M, Mallet J (1995) Transplantation to the rat brain of human neural progenitors that were geneticaly modified using adenoviruses. Nat Genet 9: 256–260. [DOI] [PubMed] [Google Scholar]
  • 66. Sah DWY, Ray J, Gage FH (1997) Bipotent progenitor cell lines from the human CNS. Nat Biotech 15: 574–580. [DOI] [PubMed] [Google Scholar]
  • 67. Saucedo‐Cardenas O, Quintana‐Hau JD, Le WD, Smidt MP, Cox JJ, De MF, Burbach JP, Conneely OM (1998) Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc Natl Acad Sci USA 95: 4013–4018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Sauer FC (1935) Mitosis in the neural tube. J Comp Neurol 62: 377–405. [Google Scholar]
  • 69. Shamblott MJ, Axelman J, Wang S, Bugg EM, Littlefield JW, Donovan PJ, Blumenthal PD, Huggins GR, Gearhart JD (1998) Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci USA 95: 13726–13731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70. Shen Q, Qian X, Capela A, Temple S (1998) Stem cells in the embryonic cerebral cortex: their role in histogenesis and patterning. J Neurobiol 36: 162–174. [PubMed] [Google Scholar]
  • 71. Smidt MP, van SH , Lanctot C, Tremblay JJ, Cox JJ, van der Kleij AA, Wolterink G, Drouin J, Burbach JP (1997) A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc Natl Acad Sci USA 94: 13305–13310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Smith A (1998) Cell therapy: in search of pluripotency. Curr Biol 8: R802–R804. [DOI] [PubMed] [Google Scholar]
  • 73. Smith AG (1992) Mouse embryo stem cells: their identification, propagation and manipulation. Semin Cell Biol 3: 385–399. [DOI] [PubMed] [Google Scholar]
  • 74. Stemple DL, Mahanthappa NK (1997) Neural stem cells are blasting off. Neuron 18: 1–4. [DOI] [PubMed] [Google Scholar]
  • 75. 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]
  • 76. Svendsen CN, Caldwell MA, Shen J, ter Borg MG, Rosser AE, Tyers P, Karmiol S, Dunnett SB (1997) Long term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinsons Disease. Exp Neuron 48: 135–146. [DOI] [PubMed] [Google Scholar]
  • 77. 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]
  • 78. Svendsen CN, Fawcett J, Bentlage C, Dunnett SB (1995) Increased survival of rat EGF‐generated CNS progenitor cells using B27 supplemented medium. Exp Brain Res 102: 407–414. [DOI] [PubMed] [Google Scholar]
  • 79. Svendsen CN, Rosser AE (1995) Neurons from stem cells TINS 18: 465–467. [DOI] [PubMed] [Google Scholar]
  • 80. Svendsen CN, Skepper JN, Rosser AE, ter Borg M, Tyers P, Ryken T (1997) Restricted growth potential of rat striatal precursors as compared to mouse. Dev Brain Res 99: 253–258. [DOI] [PubMed] [Google Scholar]
  • 81. Svendsen CN, Smith AG (1999) Human stem cell therapy. Trends Neurosci In Press. [DOI] [PubMed] [Google Scholar]
  • 82. Svendsen CN, ter Borg MG, Armstrong JE, Rosser AE, Chandran S, Ostenfeld T, Caldwell MA (1998) A new method for the rapid and long term growth of human neural precursor cells. J Neurosci Methods 85: 141–153. [DOI] [PubMed] [Google Scholar]
  • 83. Tanabe Y, Jessell TM (1996) Diversity and pattern in the developing spinal cord. Science 274: 1115–1123. [DOI] [PubMed] [Google Scholar]
  • 84. Temple S, Davis AD (1994) Isolated rat cortical progenitor cells are maintained in division in vitro by membrane‐associated factors. Development 120: 999–1008. [DOI] [PubMed] [Google Scholar]
  • 85. Temple S, Raff MC (1986) Clonal analysis of oligodendrocyte development in culture: evidence for a developmental clock that counts cell divisions. Cell 44: 773–779. [DOI] [PubMed] [Google Scholar]
  • 86. Thomson JA, Itskovitz‐Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshal VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocyts. Science 282: 1145–1147. [DOI] [PubMed] [Google Scholar]
  • 87. Voyvodic JT (1996) Cell death in cortical development: How much? Why? So what Neuron 16: 693–696. [DOI] [PubMed] [Google Scholar]
  • 88. Weiss S, Reynolds BA, Vescovi AL, Morshead CM, Craig CG, van der Kooy D (1996) Is there a neural stem cell in the mammalian forebrain. TINS 19: 387–393. [DOI] [PubMed] [Google Scholar]
  • 89. Weiss S, van der Kooy D (1998) CNS stem cells: Where's the biology (a.k.a. beef) J Neurobiol 36: 307–314. [DOI] [PubMed] [Google Scholar]
  • 90. Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH (1997) Viable offspring derived from fetal and adult mammalian cells Nature 385: 810–813. [DOI] [PubMed] [Google Scholar]
  • 91. Ye W, Shimamura K, Rubenstein JL, Hynes M, Rosenthal A (1998) FGF and Shh signals control dopaminergic and serotonergic fate in the anterior neural plate. Cell 93: 755–766. [DOI] [PubMed] [Google Scholar]
  • 92. Zhang SC, Lipsitz D, Duncan ID (1998) Self‐renewing canine oligodendroglial progenitor expanded as oligospheres. J Neurosci Res 54: 181–190. [DOI] [PubMed] [Google Scholar]
  • 93. Zhang S, Lundberg C, Lipsitz D, O'Connor LT, Duncan ID (1998) Generation of oligodendroglial progenitors from neural stem cells. J Neurocytol 27: 457–489. [DOI] [PubMed] [Google Scholar]

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