Neurogenic Astrocytes and Their Glycoconjugates: Not Just “Glue” Anymore

  • Dennis A. SteindlerEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 814)


Cells with certain attributes of very immature astroglial cells and their radial precursors can act as stem and/or progenitor cells during developmental and persistent neurogenesis. Neural stem/progenitor cells both express and are affected by a variety of developmentally regulated macromolecules and growth factors, and such signaling or recognition molecules are being uncovered through extensive genomic and proteomic studies, as well as tested using in vitro/in vivo cell growth bioassays. Glycosylated molecules are appreciated as distinct signaling molecules during morphogenesis in a variety of tissues and organs, with glycoconjugates (glycoproteins, glycolipids, and glycosaminoglycans) serving as mediators for the interactions of cells with each other and their substrates, to confer growth and differentiation cues to precursor cells in search of identity. Neurogenic astrocytes and associated glycoconjugates, especially extracellular matrix molecules, are discussed in the context of neurogenesis and stem/progenitor cell growth, fate choice, and differentiation.

Key words

Astrocyte Stem cell Extracellular matrix Multipotent astrocytic stem cell Adult human neural progenitor cell 



The author would like to thank Dr. Bjorn Scheffler for many discussions on and help with this topic, and Drs. Tong Zheng, Florian Siebzehnrubl, Oleg Suslov, Shanshan Wang, and Daniel Silver for also collaborating on all aspects of the cell and molecular biology of neural stem/progenitor cells. DAS’s research is supported by NIH grant NS055165.


  1. 1.
    Scheffler B, Horn M, Blumcke I, Laywell ED, Coomes D, Kukekov VG, Steindler DA (1999) Marrow-mindedness: a perspective on neuropoiesis. Trends Neurosci 22:348–357.PubMedCrossRefGoogle Scholar
  2. 2.
    Steindler, D.A. and D. Pincus (2002) Stem cells and neuropoiesis in the adult human brain. The Lancet 359:1047–1054.CrossRefGoogle Scholar
  3. 3.
    Laywell, E., Steindler, D.A., Silver, D.J. (2007) Astrocytic stem cells in the adult brain. Neurosurgery Clinics of North America 18:21–30.PubMedCrossRefGoogle Scholar
  4. 4.
    Garzón-Muvdi T, Quiñones-Hinojosa A. (2009) Neural stem cell niches and homing: recruitment and integration into functional tissues. ILAR J. 51:3–23.PubMedGoogle Scholar
  5. 5.
    Aimone JB, Deng W, Gage FH. (2010) Adult neurogenesis: integrating theories and separating functions. Trends Cogn Sci. 14:325–37.PubMedCrossRefGoogle Scholar
  6. 6.
    Goetz AK, Scheffler B, Chen HX, Wang S, Xiang H, Suslov O, Brustle O, Roper SN, Steindler D (2006) Temporally restricted substrate interactions direct fate and specification of neural precursors derived from embryonic stem cells. Proc Natl Acad Sci USA. 103(29):11063–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Faissner A, Steindler D (1995) Boundaries and inhibitory molecules in developing neural tissues. Glia 13:233–54.PubMedCrossRefGoogle Scholar
  8. 8.
    Steindler DA (1993) Glial boundaries in the developing nervous system. Annu Rev Neurosci 16:445–470.PubMedCrossRefGoogle Scholar
  9. 9.
    Gates MA, Thomas LB, Howard EM, Laywell ED, Sajin B, Faissner A, Götz B, Silver J, Steindler DA.(1995) Cell and molecular analysis of the developing and adult mouse subventricular zone of the cerebral hemispheres. J Comp Neurol. 361:249–66.PubMedCrossRefGoogle Scholar
  10. 10.
    Thomas LB, Gates MA, Steindler DA. (1996) Young neurons from the adult subependymal zone proliferate and migrate along an astrocyte, extracellular matrix-rich pathway. Glia. 17:1–14PubMedCrossRefGoogle Scholar
  11. 11.
    Yu RK, Yanagisawa M (2007) Glycosignaling in neural stem cells: involvement of glycoconjugates in signal transduction modulating the neural stem cell fate. J. Neurochem. 103 (Supp 1):39–46.PubMedCrossRefGoogle Scholar
  12. 12.
    Yanagisawa M, Yu RK. (2007) The expression and functions of glycoconjugates in neural stem cells. Glycobiology 17:57R–74R.PubMedCrossRefGoogle Scholar
  13. 13.
    Yu RK, Suzuki Y, Yanagisawa M. (2010) Membrane glycolipids in stem cells. FEBS Lett. 584:1694–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Tsai RY, Kittappa R, McKay RD. (2002) Plasticity, niches, and the use of stem cells. Dev Cell. 2:707–12.PubMedCrossRefGoogle Scholar
  15. 15.
    Steindler, D.A., N.G.F. Cooper, A. Faissner and M. Schachner. Boundaries defined by adhesion molecules during development of the cerebral cortex: The J1/tenascin glycoprotein in the mouse somatosensory cortical barrel field. Developmental Biology 131:243–260, 1989.PubMedCrossRefGoogle Scholar
  16. 16.
    Doetsch F, Caillé I, Lim DA, García-Verdugo JM, Alvarez-Buylla A. (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 97(6):703–16.PubMedCrossRefGoogle Scholar
  17. 17.
    Laywell ED, Rakic P, Kukekov VG, Holland EC, Steindler DA (2000) Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci USA 97:13883–13888.PubMedCrossRefGoogle Scholar
  18. 18.
    Garcia AD, Doan NB, Imura T, Bush TG, Sofroniew MV. (2004) GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat. Neurosci. 7:1233–41.PubMedCrossRefGoogle Scholar
  19. 19.
    Liu X, Bolteus AJ, Balkin DM, Henschel O, Bordey A. (2006) GFAP-expressing cells in the postnatal subventricular zone display a unique glial phenotype intermediate between radial glia and astrocytes. Glia 54:394–410.PubMedCrossRefGoogle Scholar
  20. 20.
    Cooper NG, Steindler DA (1989) Critical period-dependent alterations of the transient body image in the rodent cerebral cortex. Brain Res 489:167–176.PubMedCrossRefGoogle Scholar
  21. 21.
    Steindler DA, Faissner A, Harrington KL (1994) A unique mosaic in the visual cortex of the reeler mutant mouse. Cereb Cortex 4:129–137.PubMedCrossRefGoogle Scholar
  22. 22.
    Scheffler B, Faissner A, Beck H, Behle K, Wolfe HK, Wiestler O, Bluemcke I (1997) Hippocampal loss of tenascin boundaries in Ammon’s horn sclerosis. Glia 19:35–46.PubMedCrossRefGoogle Scholar
  23. 23.
    Dityatev A, Schachner M (2003) Extracellular matrix molecules and synaptic plasticity. Nat Rev Neurosci 4:456–468.PubMedCrossRefGoogle Scholar
  24. 24.
    Kearns SM, Scheffler B, Goetz AK, Lin DD, Baker HD, Roper SN, Mandel RJ, Steindler DA (2006) A method for a more complete in vitro Parkinson’s model: slice culture bioassay for modeling maintenance and repair of the nigrostriatal circuit. J Neurosci Methods. 157:1–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Kukekov VG, Laywell ED, Suslov O, Davies K, Scheffler B, Thomas LB, O’Brien TF, Kusakabe M, Steindler DA (1999) Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain. Exp Neurol 156:333–44.PubMedCrossRefGoogle Scholar
  26. 26.
    Kearns SM, Laywell ED, Kukekov VK, Steindler DA (2003) Extracellular matrix effects on neurosphere cell motility. Exp Neurol 182:240–244.PubMedCrossRefGoogle Scholar
  27. 27.
    Hagg T (2005) Molecular regulation of adult CNS neurogenesis: an integrated view. Trends Neurosci 28:589–595.PubMedCrossRefGoogle Scholar
  28. 28.
    Alvarez-Buylla A, Lim DA (2004) For the long run: maintaining germinal niches in the adult brain. Neuron 41:683–686.PubMedCrossRefGoogle Scholar
  29. 29.
    Imura T, Kornblum HI, Sofroniew MV. (2003) The predominant neural stem cell isolated from postnatal and adult forebrain but not early embryonic forebrain expresses GFAP. J Neurosci. 23:2824–32.PubMedGoogle Scholar
  30. 30.
    Seri B, García-Verdugo JM, McEwen BS, Alvarez-Buylla A. (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci. 21:7153–60.PubMedGoogle Scholar
  31. 31.
    van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034.PubMedCrossRefGoogle Scholar
  32. 32.
    Chiasson BJ, Tropepe V, Morshead CM, van der Kooy D (1999) Adult mammalian forebrain ependymal and subependymal cells demonstrate proliferative potential, but only subependymal cells have neural stem cell characteristics. J Neurosci. 19:4462–71.PubMedGoogle Scholar
  33. 33.
    Zheng T, Marshall GP 2nd, Laywell ED, Steindler DA. (2006) Neurogenic astrocytes transplanted into the adult mouse lateral ventricle contribute to olfactory neurogenesis, and reveal a novel intrinsic subependymal neuron. Neuroscience 142:175–85.PubMedCrossRefGoogle Scholar
  34. 34.
    Zheng T, Rossignol C, Leibovici, Anderson KJ, Steindler DA, Weiss MD (2006) Transplantation of multipotent astrocytic stem cells into a rat model of neonatal hypoxic-ischemic encephalopathy. Brain Res 1112:99–105.PubMedCrossRefGoogle Scholar
  35. 35.
    Walton NM, Sutter BM, Chen HX, Chang LJ, Roper SN, Scheffler B, Steindler DA. (2006) Derivation and large-scale expansion of multipotent astroglial neural progenitors from adult human brain. Development 133:3671–81.PubMedCrossRefGoogle Scholar
  36. 36.
    Merkle FT, Tramontin AD, García-Verdugo JM, Alvarez-Buylla A. (2004) Radial glia give rise to adult neural stem cells in the subventricular zone. Proc Natl Acad Sci USA. 101:17528–32.PubMedCrossRefGoogle Scholar
  37. 37.
    Merkle FT, Mirzadeh Z, Alvarez-Buylla A. (2007) Mosaic organization of neural stem cells in the adult brain. Science 317:381–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Doetsch F, García-Verdugo JM, Alvarez-Buylla A. (1997) Cellular composition and three-dimensional organization of the subventricular germinal zone in the adult mammalian brain. J Neurosci. 17:5046–61.PubMedGoogle Scholar
  39. 39.
    Kishi K. (1987) Golgi studies on the development of granule cells of the rat olfactory bulb with reference to migration in the subependymal layer. J Comp Neurol. 258:112–24.PubMedCrossRefGoogle Scholar
  40. 40.
    Petreanu L, Alvarez-Buylla A. (2002) Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction. J Neurosci. 22:6106–13.PubMedGoogle Scholar
  41. 41.
    Danilov AI, Gomes-Leal W, Ahlenius H, Kokaia Z, Carlemalm E, Lindvall O. (2009) Ultrastructural and antigenic properties of neural stem cells and their progeny in adult rat subventricular zone. Glia. 57:136–52.PubMedCrossRefGoogle Scholar
  42. 42.
    Scheffler B, Walton NM, Lin DD, Goetz AK, Enikolopov G, Roper SN, Steindler DA (2005) Phenotypic and functional characterization of adult brain neuropoiesis. Proc Natl Acad Sci USA 102:9353–9358.PubMedCrossRefGoogle Scholar
  43. 43.
    Palmer TD, Willhoite AR, Gage FH.(2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol. 425:479–94.PubMedCrossRefGoogle Scholar
  44. 44.
    Shen Q, Wang Y, Kokovay E, Lin G, Chuang SM, Goderie SK, Roysam B, Temple S (2008) Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3:289–300.PubMedCrossRefGoogle Scholar
  45. 45.
    Kerever A, Schnack J, Vellinga D, Ichikawa N, Moon C, Arikawa-Hirasawa E, Efird JT, Mercier F. (2007) Novel extracellular matrix structures in the neural stem cell niche capture the neurogenic factor fibroblast growth factor 2 from the extracellular milieu. Stem Cells. 25:2146–57.PubMedCrossRefGoogle Scholar
  46. 46.
    Campbell K (2005) Cortical neuron specification: it has its time and place. Neuron 46:373–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Sur M, Rubenstein JL. (2005) Patterning and plasticity of the cerebral cortex. Science. 310:805–10.PubMedCrossRefGoogle Scholar
  48. 48.
    Nunes MC, Roy NS, Keyoung HM, Goodman RR, McKhann G 2nd, Jiang L, Kang J, Nedergaard M, Goldman SA. (2003) Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat Med. 9:439–47.PubMedCrossRefGoogle Scholar
  49. 49.
    Zheng T, Steindler DA, Laywell ED (2002) Transplantation of an indigenous neural stem cell population leading to hyperplasia and atypical integration. Cloning Stem Cells 4:3–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, Mori T, Götz M (2008) Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain. Proc Natl Acad Sci USA. 105:3581–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Brodkey JA, Gates MA, Laywell ED, Steindler DA (1993) The complex nature of interactive neuroregeneration-related molecules. Exp Neurol 123:251–270.PubMedCrossRefGoogle Scholar
  52. 52.
    Noctor SC, Flint AC, Weissman TA, Wong WS, Clinton BK, Kriegstein AR (2002) Dividing precursor cells of the embryonic cortical ventricular zone have morphological and molecular characteristics of radial glia. J Neurosci 22:3161–3173.PubMedGoogle Scholar
  53. 53.
    Steindler DA, Laywell ED. (2003).Astrocytes as stem cells: nomenclature, phenotype, and translation. Glia. 43:62–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Hansen DV, Lui JH, Parker PR, Kriegstein AR (2010).Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature. 464:554–561.PubMedCrossRefGoogle Scholar
  55. 55.
    Rietze RL, Valcanis H, Brooker GF, Thomas T, Voss AK, Bartlett PF. (2001) Purification of a pluripotent neural stem cell from the adult mouse brain. Nature. 16:736–9.CrossRefGoogle Scholar
  56. 56.
    Liu Y, Han SS, Wu Y, Tuohy TM, Xue H, Cai J, Back SA, Sherman LS, Fischer I, Rao MS. (2004) CD44 expression identifies astrocyte-restricted precursor cells. Dev Biol. 276:31–46.PubMedCrossRefGoogle Scholar
  57. 57.
    Capela A, Temple S. (2002) LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron. 35:865–75.PubMedCrossRefGoogle Scholar
  58. 58.
    Nishiyama A, Komitova M, Suzuki R, Zhu X. (2010) Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat Rev Neurosci. 10:9–22. CrossRefGoogle Scholar
  59. 59.
    Siebzehnrubl FA, Jeske I, Müller D, Buslei R, Coras R, Hahnen E, Huttner HB, Corbeil D, Kaesbauer J, Appl T, von Hörsten S, Blümcke I. (2009) Spontaneous in vitro transformation of adult neural precursors into stem-like cancer cells. Brain Pathol. 19:399–408.PubMedCrossRefGoogle Scholar
  60. 60.
    Garcion E, Halilagic A, Faissner A, ffrench-Constant C.(2004) Generation of an environmental niche for neural stem cell development by the extracellular matrix molecule tenascin C. Development. 131:3423–32.PubMedCrossRefGoogle Scholar
  61. 61.
    von Holst A, Sirko S, Faissner A. (2006) The unique 473HD-Chondroitinsulfate epitope is expressed by radial glia and involved in neural precursor cell proliferation. J Neurosci. 26:4082–94.CrossRefGoogle Scholar
  62. 62.
    Suslov ON, Kukekov VG, Ignatova TN, Steindler DA. (2002) Neural stem cell heterogeneity demonstrated by molecular phenotyping of clonal neurospheres. Proc Natl Acad Sci U S A. 99:14506–11.PubMedCrossRefGoogle Scholar
  63. 63.
    Ignatova, T., V.G. Kukekov, E.D. Laywell, O.N. Suslov, F. Vrionis, and D.A. Steindler. (2002) Human cortical glial tumors contain stem-like cells expressing astroglial and neuronal markers in vitro. Glia 39:193–206.PubMedCrossRefGoogle Scholar
  64. 64.
    Singh S, Dirks PB. (2007) Brain tumor stem cells: identification and concepts. Neurosurg Clin N Am. 18:31–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Brakebusch C, Fässler R. (2003) The integrin-actin connection, an eternal love affair. EMBO J. 22:2324–33.PubMedCrossRefGoogle Scholar
  66. 66.
    Lendahl U, Zimmerman LB, McKay RD. (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60:585–95.PubMedCrossRefGoogle Scholar
  67. 67.
    Middeldorp J, Boer, K, Slukis JA, De Filippis L, Encha-Razavi F, Vescovi AL, Swaab DF, Aronica E, Hol EM. (2010) GFAPdelta in radial glia and subventricular zone progenitors in the developing human cortex. Development. 137:313–21.PubMedCrossRefGoogle Scholar
  68. 68.
    Reynolds BA, and Weiss S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–10.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Neuroscience, The Evelyn F. and William L. McKnight Brain InstituteThe University of FloridaGainesvilleUSA

Personalised recommendations