Neural progenitor diversity and their therapeutic potential for spinal cord repair

Abstract

Development of the central nervous system (CNS) requires progressive differentiation of neural stem cells, which generate a variety of neural progenitors with distinct properties and differentiation potentials in a spatiotemporally restricted manner. The underlying mechanisms of neural progenitor diversification during development started to be unraveled over the past years. We have addressed these questions by v-myc immortalization method and generation of neural progenitor clones. These clones are served as in vitro models of neural differentiation and cellular tools for transplantation in animal models of neurological disorders including spinal cord injury. In this review, we will discuss features of two neural progenitor types (radial glia and GABAergic interneuron progenitor) and diversification even within each progenitor type. We will also discuss pathophysiology of spinal cord injury and our ongoing research to address both motor and sensory malfunctions by transplantation of these neural progenitors.

Key words： neural progenitors; diversity; radial glia; interneuron progenitor; spinal cord injury; cell transplantation

Acknowledgements

This work was supported by grants from the New Jersey Commission on Spinal Cord Research and National Natural Science Foundation of China.

References

1 Anderson S A, Eisenstat D D, Shi L, Rubenstein J L (1997). Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science, 278(5337): 474–476

2 Anton E S, Kreidberg J A, Rakic P (1999). Distinct functions of alpha3 and alpha(v) integrin receptors in neuronal migration and laminar organization of the cerebral cortex. Neuron, 22(2): 277–289

3 Ascoli G A, Alonso-Nanclares L, Anderson S A, Barrionuevo G, Benavides-Piccione R, Burkhalter A, Buzsáki G, Cauli B, Defelipe J, Fairén A, Feldmeyer D, Fishell G, Fregnac Y, Freund TF, Gardner D, Gardner E P, Goldberg J H, Helmstaedter M, Hestrin S, Karube F, Kisvárday ZF, Lambolez B, Lewis D A, Marin O, Markram H, Muñoz A, Packer A, Petersen C C, Rockland K S, Rossier J, Rudy B, Somogyi P, Staiger J F, Tamas G, Thomson A M, Toledo-Rodriguez M, Wang Y, West D C, Yuste R (2008). Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat Rev Neurosci, 9: 557–568

4 Babcock A A, Kuziel W A, Rivest S, Owens T (2003). Chemokine expression by glial cells directs leukocytes to sites of axonal injury in the CNS. J Neurosci, 23(21): 7922–7930

5 Beattie M S, Hermann G E, Rogers R C, Bresnahan J C (2002). Cell death in models of spinal cord injury. Prog Brain Res, 137: 37–47

6 Beck K D, Nguyen H X, Galvan M D, Salazar D L, Woodruff T M, Anderson A J (2010). Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain, 133(Pt 2): 433–447

7 Becker A J, McCULLOCH E A, Till J E (1963). Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature, 197: 452–454

8 Bracken M B (2002). Steroids for acute spinal cord injury. Cochrane Database Syst Rev, (3): CD001046

9 Braughler J M, Duncan L A, Chase R L (1985). Interaction of lipid peroxidation and calcium in the pathogenesis of neuronal injury. Cent Nerv Syst Trauma, 2(4): 269–283

10 Bunge M B (1994). Transplantation of purified populations of Schwann cells into lesioned adult rat spinal cord. J Neurol, 242(1 Suppl 1): S36–S39

11 Busch S A, Silver J (2007). The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol, 17(1): 120–127

12 Butt S J, Sousa V H, Fuccillo M V, Hjerling-Leffler J, Miyoshi G, Kimura S, Fishell G (2008). The requirement of Nkx2-1 in the temporal specification of cortical interneuron subtypes. Neuron, 59(5): 722–732

13 Cai J, Wu Y, Mirua T, Pierce J L, Lucero M T, Albertine K H, Spangrude G J, Rao M S (2002). Properties of a fetal multipotent neural stem cell (NEP cell). Dev Biol, 251(2): 221–240

14 Cao Q L, Howard R M, Dennison J B, Whittemore S R (2002). Differentiation of engrafted neuronal-restricted precursor cells is inhibited in the traumatically injured spinal cord. Exp Neurol, 177(2): 349–359

15 Cao Q L, Zhang Y P, Howard R M, Walters W M, Tsoulfas P, Whittemore S R (2001). Pluripotent stem cells engrafted into the normal or lesioned adult rat spinal cord are restricted to a glial lineage. Exp Neurol, 167(1): 48–58

16 Chang Y W, Goff L A, Li H, Kane-Goldsmith N, Tzatzalos E, Hart R P, Young W, Grumet M (2009). Rapid induction of genes associated with tissue protection and neural development in contused adult spinal cord after radial glial cell transplantation. J Neurotrauma, 26(7): 979–993

17 Cobos I, Borello U, Rubenstein J L (2007). Dlx transcription factors promote migration through repression of axon and dendrite growth. Neuron, 54(6): 873–888

18 Corbin J G, Gaiano N, Juliano S L, Poluch S, Stancik E, Haydar T F (2008). Regulation of neural progenitor cell development in the nervous system. J Neurochem, 106(6): 2272–2287

19 De Filippis L, Lamorte G, Snyder E Y, Malgaroli A, Vescovi A L (2007). A novel, immortal, and multipotent human neural stem cell line generating functional neurons and oligodendrocytes. Stem Cells, 25(9): 2312–2321

20 Eaton M J, Wolfe S Q, Martinez M, Hernandez M, Furst C, Huang J, Frydel B R, Gómez-Marín O (2007). Subarachnoid transplant of a human neuronal cell line attenuates chronic allodynia and hyperalgesia after excitotoxic spinal cord injury in the rat. J Pain, 8(1): 33–50

21 Evans M J, Kaufman M H (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819): 154–156

22 Frederiksen K, Jat P S, Valtz N, Levy D, McKay R (1988). Immortalization of precursor cells from the mammalian CNS. Neuron, 1(6): 439–448

23 Frisa P S, Goodman M N, Smith G M, Silver J, Jacobberger J W (1994). Immortalization of immature and mature mouse astrocytes with SV40 T antigen. J Neurosci Res, 39(1): 47–56

24 Gage F H (2000). Mammalian neural stem cells. Science, 287(5457): 1433–1438

25 Gaiano N, Nye J S, Fishell G (2000). Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron, 26(2): 395–404

26 Gonchar Y, Burkhalter A (1997). Three distinct families of GABAergic neurons in rat visual cortex. Cereb Cortex, 7: 347–358

27 Götz M, Stoykova A, Gruss P (1998). Pax6 controls radial glia differentiation in the cerebral cortex. Neuron, 21(5): 1031–1044

28 Gulacsi A, Lillien L (2003). Sonic hedgehog and bone morphogenetic protein regulate interneuron development from dorsal telencephalic progenitors in vitro. J Neurosci, 23(30): 9862–9872

29 Hains B C, Klein J P, Saab C Y, Craner M J, Black J A, Waxman S G (2003). Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci, 23(26): 8881–8892

30 Hall E D (2001). Pharmacological treatment of acute spinal cord injury: how do we build on past success? J Spinal Cord Med, 24(3): 142–146

31 Hansen D V, Lui J H, Parker P R, Kriegstein A R (2010). Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature, 464(7288): 554–561

32 Hao J X, Xu X J, Yu Y X, Seiger A, Wiesenfeld-Hallin Z (1992). Baclofen reverses the hypersensitivity of dorsal horn wide dynamic range neurons to mechanical stimulation after transient spinal cord ischemia; implications for a tonic GABAergic inhibitory control of myelinated fiber input. J Neurophysiol, 68(2): 392–396

33 Hasegawa K, Chang Y W, Li H, Berlin Y, Ikeda O, Kane-Goldsmith N, Grumet M (2005). Embryonic radial glia bridge spinal cord lesions and promote functional recovery following spinal cord injury. Exp Neurol, 193(2): 394–410

34 Heins N, Malatesta P, Cecconi F, Nakafuku M, Tucker K L, Hack M A, Chapouton P, Barde Y A, Götz M (2002). Glial cells generate neurons: the role of the transcription factor Pax6. Nat Neurosci, 5(4): 308–315

35 Hill C E, Proschel C, Noble M, Mayer-Proschel M, Gensel J C, Beattie M S, Bresnahan J C (2004). Acute transplantation of glial-restricted precursor cells into spinal cord contusion injuries: survival, differentiation, and effects on lesion environment and axonal regeneration. Exp Neurol, 190(2): 289–310

36 Hofstetter C P, Holmström N A, Lilja J A, Schweinhardt P, Hao J, Spenger C, Wiesenfeld-Hallin Z, Kurpad S N, Frisén J, Olson L (2005). Allodynia limits the usefulness of intraspinal neural stem cell grafts; directed differentiation improves outcome. Nat Neurosci, 8(3): 346–353

37 Hulsebosch C E (2005). From discovery to clinical trials: treatment strategies for central neuropathic pain after spinal cord injury. Curr Pharm Des, 11(11): 1411–1420

38 Imaizumi T, Lankford K L, Kocsis J D (2000). Transplantation of olfactory ensheathing cells or Schwann cells restores rapid and secure conduction across the transected spinal cord. Brain Res, 854(1–2): 70–78

39 Keirstead H S, Morgan S V, Wilby M J, Fawcett J W (1999). Enhanced axonal regeneration following combined demyelination plus schwann cell transplantation therapy in the injured adult spinal cord. Exp Neurol, 159(1): 225–236

40 Kim J H, Auerbach J M, Rodríguez-Gómez J A, Velasco I, Gavin D, Lumelsky N, Lee S H, Nguyen J, Sánchez-Pernaute R, Bankiewicz K, McKay R (2002). Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature, 418(6893): 50–56

41 Kohama I, Lankford K L, Preiningerova J, White F A, Vollmer T L, Kocsis J D (2001). Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J Neurosci, 21(3): 944–950

42 Kriegstein A R, Götz M (2003). Radial glia diversity: a matter of cell fate. Glia, 43(1): 37–43

43 Kumagai G, Okada Y, Yamane J, Nagoshi N, Kitamura K, Mukaino M, Tsuji O, Fujiyoshi K, Katoh H, Okada S, Shibata S, Matsuzaki Y, Toh S, Toyama Y, Nakamura M, Okano H (2009). Roles of ES cell-derived gliogenic neural stem/progenitor cells in functional recovery after spinal cord injury. PLoS One, 4(11): e7706

44 Larsen K B, Lutterodt M C, Laursen H, Graem N, Pakkenberg B, Møllgård K, Møller M (2010). Spatiotemporal distribution of PAX6 and MEIS2 expression and total cell numbers in the ganglionic eminence in the early developing human forebrain. Dev Neurosci, 32(2): 149–162

45 Lee H J, Lee J K, Lee H, Shin J W, Carter J E, Sakamoto T, Jin H K, Bae J S (2010). The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer’s disease. Neurosci Lett, 481(1): 30–35

46 Li H, Babiarz J, Woodbury J, Kane-Goldsmith N, Grumet M (2004). Spatiotemporal heterogeneity of CNS radial glial cells and their transition to restricted precursors. Dev Biol, 271(2): 225–238

47 Li H, Chang Y W, Mohan K, Su H W, Ricupero C L, Baridi A, Hart R P, Grumet M (2008a). Activated Notch1 maintains the phenotype of radial glial cells and promotes their adhesion to laminin by upregulating nidogen. Glia, 56(6): 646–658

48 Li H, Grumet M (2007). BMP and LIF signaling coordinately regulate lineage restriction of radial glia in the developing forebrain. Glia, 55: 24–35

49 Li H, Han Y R, Bi C, Davila J, Goff L A, Thompson K, Swerdel M, Camarillo C, Ricupero C L, Hart R P, Plummer M R, Grumet M (2008b). Functional differentiation of a clone resembling embryonic cortical interneuron progenitors. Dev Neurobiol, 68(14): 1549–1564

50 Linderoth B, Stiller C O, Gunasekera L, O’Connor W T, Ungerstedt U, Brodin E (1994). Gamma-aminobutyric acid is released in the dorsal horn by electrical spinal cord stimulation: an in vivo microdialysis study in the rat. Neurosurgery, 34(3): 484–488, discussion 488–489

51 Liu Y, Wu Y, Lee J C, Xue H, Pevny L H, Kaprielian Z, Rao M S (2002). Oligodendrocyte and astrocyte development in rodents: an in situ and immunohistological analysis during embryonic development. Glia, 40(1): 25–43

52 Loulier K, Lathia J D, Marthiens V, Relucio J, Mughal M R, Tang S C, Coksaygan T, Hall P E, Chigurupati S, Patton B, Colognato H, Rao M S, Mattson M P, Haydar T F, Ffrench-Constant C (2009). beta1 integrin maintains integrity of the embryonic neocortical stem cell niche. PLoS Biol, 7(8): e1000176

53 Lu P, Jones L L, Snyder E Y, Tuszynski M H (2003). Neural stem cells constitutively secrete neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp Neurol, 181(2): 115–129

54 Lu Q R, Sun T, Zhu Z, Ma N, Garcia M, Stiles C D, Rowitch D H (2002). Common developmental requirement for Olig function indicates a motor neuron/oligodendrocyte connection. Cell, 109(1): 75–86

55 Lu Q R, Yuk D, Alberta J A, Zhu Z, Pawlitzky I, Chan J, McMahon A P, Stiles C D, Rowitch D H (2000). Sonic hedgehog—regulated oligodendrocyte lineage genes encoding bHLH proteins in the mammalian central nervous system. Neuron, 25(2): 317–329

56 Malatesta P, Hack M A, Hartfuss E, Kettenmann H, Klinkert W, Kirchhoff F, Götz M (2003). Neuronal or glial progeny: regional differences in radial glia fate. Neuron, 37(5): 751–764

57 Malatesta P, Hartfuss E, Götz M (2000). Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development, 127(24): 5253–5263

58 Marchal L, Luxardi G, Thomé V, Kodjabachian L (2009). BMP inhibition initiates neural induction via FGF signaling and Zic genes. Proc Natl Acad Sci U S A, 106(41): 17437–17442

59 Martin G R (1981). Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci U S A, 78(12): 7634–7638

60 Mayer-Proschel M, Kalyani A J, Mujtaba T, Rao M S (1997). Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron, 19(4): 773–785

61 McDonald J W, Liu X Z, Qu Y, Liu S, Mickey S K, Turetsky D, Gottlieb D I, Choi D W (1999). Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord. Nat Med, 5(12): 1410–1412

62 Mehler M F (2002). Mechanisms regulating lineage diversity during mammalina cerebral cortical neurogenesis and gliogenesis. In: Hohmann C F, ed. Cortical Development, Berlin: Springer-Verlag. 27–52

63 Meisner J G, Marsh A D, Marsh D R (2010). Loss of GABAergic interneurons in laminae I-III of the spinal cord dorsal horn contributes to reduced GABAergic tone and neuropathic pain after spinal cord injury. J Neurotrauma, 27(4): 729–737

64 Meletis K, Barnabé-Heider F, Carlén M, Evergren E, Tomilin N, Shupliakov O, Frisén J (2008). Spinal cord injury reveals multilineage differentiation of ependymal cells. PLoS Biol, 6(7): e182

65 Mi R, Luo Y, Cai J, Limke T L, Rao M S, Höke A (2005). Immortalized neural stem cells differ from nonimmortalized cortical neurospheres and cerebellar granule cell progenitors. Exp Neurol, 194(2): 301–319

66 Miyata T, Kawaguchi A, Okano H, Ogawa M (2001). Asymmetric inheritance of radial glial fibers by cortical neurons. Neuron, 31(5): 727–741

67 Miyoshi G, Butt S J, Takebayashi H, Fishell G (2007). Physiologically distinct temporal cohorts of cortical interneurons arise from telencephalic Olig2-expressing precursors. J Neurosci, 27(29): 7786–7798

68 Mizutani K, Yoon K, Dang L, Tokunaga A, Gaiano N (2007). Differential Notch signalling distinguishes neural stem cells from intermediate progenitors. Nature, 449(7160): 351–355

69 Moreno-Manzano V, Rodríguez-Jiménez F J, García-Roselló M, Laínez S, Erceg S, Calvo M T, Ronaghi M, Lloret M, Planells-Cases R, Sánchez-Puelles J M, Stojkovic M (2009). Activated spinal cord ependymal stem cells rescue neurological function. Stem Cells, 27(3): 733–743

70 Mukhida K, Mendez I, McLeod M, Kobayashi N, Haughn C, Milne B, Baghbaderani B, Sen A, Behie L A, Hong M (2007). Spinal GABAergic transplants attenuate mechanical allodynia in a rat model of neuropathic pain. Stem Cells, 25(11): 2874–2885

71 Naik A K, Pathirathna S, Jevtovic-Todorovic V (2008). GABAA receptor modulation in dorsal root ganglia in vivo affects chronic pain after nerve injury. Neuroscience, 154(4): 1539–1553

72 Noble M, Pröschel C, Mayer-Pröschel M (2004). Getting a GR(i)P on oligodendrocyte development. Dev Biol, 265(1): 33–52

73 Noctor S C, Flint A C, Weissman T A, Dammerman R S, Kriegstein A R (2001). Neurons derived from radial glial cells establish radial units in neocortex. Nature, 409(6821): 714–720

74 Noctor S C, Flint A C, Weissman T A, Wong W S, Clinton B K, Kriegstein A R (2002). Dividing precursor cells of the embryonic cortical ventricular zone have morphological and molecular characteristics of radial glia. J Neurosci, 22(8): 3161–3173

75 Norenberg M D, Smith J, Marcillo A (2004). The pathology of human spinal cord injury: defining the problems. J Neurotrauma, 21(4): 429–440

76 Olson J K (2010). Immune response by microglia in the spinal cord. Ann N Y Acad Sci, 1198: 271–278

77 Pal R, Gopinath C, Rao N M, Banerjee P, Krishnamoorthy V, Venkataramana N K, Totey S (2010) Functional recovery after transplantation of bone marrow-derived human mesenchymal stromal cells in a rat model of spinal cord injury. Cytotherapy, 2010<month>Jun</month><day>4</day>. [Epub ahead of print]

78 Panchision D M, McKay R D (2002). The control of neural stem cells by morphogenic signals. Curr Opin Genet Dev, 12(4): 478–487

79 Park D H, Lee J H, Borlongan C V, Sanberg P R, Chung Y G, Cho T H (2010). Transplantation of umbilical cord blood stem cells for treating spinal cord injury. Stem Cell Rev. DOI: 10.1007/s12015-010-9163-0

80 Pineau I, Lacroix S (2007). Proinflammatory cytokine synthesis in the injured mouse spinal cord: multiphasic expression pattern and identification of the cell types involved. J Comp Neurol, 500(2): 267–285

81 Pinto L, Götz M (2007). Radial glial cell heterogeneity—the source of diverse progeny in the CNS. Prog Neurobiol, 83(1): 2–23

82 Rakic P (1990). Principles of neural cell migration. Experientia, 46(9): 882–891

83 Rakic P J (1971). Neuron-glia relationship during granule cell migration in developing cerebellar cortex. A Golgi and electronmicroscopic study in Macacus Rhesus. J Comp Neurol, 141(3): 283–312

84 Ramón-Cueto A, Cordero M I, Santos-Benito F F, Avila J (2000). Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron, 25(2): 425–435

85 Rothman S M, Olney J W (1986). Glutamate and the pathophysiology of hypoxic—ischemic brain damage. Ann Neurol, 19(2): 105–111

86 Ryu M Y, Lee M A, Ahn Y H, Kim K S, Yoon S H, Snyder E Y, Cho K G, Kim S U (2005). Brain transplantation of neural stem cells cotransduced with tyrosine hydroxylase and GTP cyclohydrolase 1 in Parkinsonian rats. Cell Transplant, 14(4): 193–202

87 Schweigreiter R, Bandtlow C E (2006). Nogo in the injured spinal cord. J Neurotrauma, 23(3–4): 384–396

88 Shields S A, Blakemore W F, Franklin R J (2000). Schwann cell remyelination is restricted to astrocyte-deficient areas after transplantation into demyelinated adult rat brain. J Neurosci Res, 60(5): 571–578

89 Shihabuddin L S, Horner P J, Ray J, Gage F H (2000). Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. J Neurosci, 20(23): 8727–8735

90 Sibbe M, Förster E, Basak O, Taylor V, Frotscher M (2009). Reelin and Notch1 cooperate in the development of the dentate gyrus. J Neurosci, 29(26): 8578–8585

91 Siddall P J, Taylor D A, McClelland J M, Rutkowski S B, Cousins M J (1999). Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury. Pain, 81(1–2): 187–197

92 Spiropoulos A, Theodosaki M, Stefanaki K, Paterakis G, Tzetis M, Giannikou K, Petrakou E, Dimopoulou MN, Papassotiriou I, Roma ES, Kanavakis E, Graphakos S, Goussetis E (2010). Rapid clinical-scale propagation of mesenchymal stem cells using cultures initiated with immunoselected bone marrow CD105 cells. J Cell Mol Med. 2010<month>Aug</month><day>20</day>. [Epub ahead of print]

93 Sugimori M, Nagao M, Bertrand N, Parras C M, Guillemot F, Nakafuku M (2007). Combinatorial actions of patterning and HLH transcription factors in the spatiotemporal control of neurogenesis and gliogenesis in the developing spinal cord. Development, 134(8): 1617–1629

94 Tanaka D H, Mikami S, Nagasawa T, Miyazaki J I, Nakajima K, Murakami F (2010). CXCR4 is required for proper regional and laminar distribution of cortical somatostatin-, calretinin-, and neuropeptide y-expressing GABAergic interneurons. Cereb Cortex. 2010<month>Mar</month><day>3</day>. [Epub ahead of print]

95 Temple S (2001). Stem cell plasticity—building the brain of our dreams. Nat Rev Neurosci, 2(7): 513–520

96 Till J E, McCULLOCH E A (1961). A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res, 14: 213–222

97 Tsuji O, Miura K, Okada Y, Fujiyoshi K, Mukaino M, Nagoshi N, Kitamura K, Kumagai G, Nishino M, Tomisato S, Higashi H, Nagai T, Katoh H, Kohda K, Matsuzaki Y, Yuzaki M, Ikeda E, Toyama Y, Nakamura M, Yamanaka S, Okano H (2010). Therapeutic potential of appropriately evaluated safe-induced pluripotent stem cells for spinal cord injury. Proc Natl Acad Sci U S A, 107(28): 12704–12709

98 Villa A, Snyder E Y, Vescovi A, Martínez-Serrano A (2000). Establishment and properties of a growth factor-dependent, perpetual neural stem cell line from the human CNS. Exp Neurol, 161(1): 67–84

99 Wonders C P, Anderson S A (2006). The origin and specification of cortical interneurons. Nat Rev Neurosci, 7(9): 687–696

100 Wonders C P, Taylor L, Welagen J, Mbata I C, Xiang J Z, Anderson S A (2008). A spatial bias for the origins of interneuron subgroups within the medial ganglionic eminence. Dev Biol, 314(1): 127–136

101 Woo N H, Lu B (2006). Regulation of cortical interneurons by neurotrophins: from development to cognitive disorders. Neuroscientist, 12(1): 43–56

102 Woodbury D, Schwarz E J, Prockop D J, Black I B (2000). Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res, 61(4): 364–370

103 Wu G, Gentile L, Do J T, Cantz T, Sutter J, Psathaki K, Arauzo-Bravo M J, Ortmeier C, Scholer H (2010). Efficient derivation of pluripotent stem cells from sirna-mediated cdx2-deficient mouse embryos. Stem Cells Dev. 2010<month>Jun</month><day>10</day>. [Epub ahead of print]

104 Xu Q, Cobos I, De La Cruz E, Rubenstein J L, Anderson S A (2004). Origins of cortical interneuron subtypes. J Neurosci, 24(11): 2612–2622

105 Xu Q, Guo L, Moore H, Waclaw R R, Campbell K, Anderson S A (2010). Sonic hedgehog signaling confers ventral telencephalic progenitors with distinct cortical interneuron fates. Neuron, 65(3): 328–340

106 Yan J, Welsh A M, Bora S H, Snyder E Y, Koliatsos V E (2004). Differentiation and tropic/trophic effects of exogenous neural precursors in the adult spinal cord. J Comp Neurol, 480(1): 101–114

107 Yang M, Donaldson A E, Jiang Y, Iacovitti L (2003). Factors influencing the differentiation of dopaminergic traits in transplanted neural stem cells. Cell Mol Neurobiol, 23(4–5): 851–864

108 Ying Q L, Stavridis M, Griffiths D, Li M, Smith A (2003). Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat Biotechnol, 21(2): 183–186

109 Young W, Koreh I (1986). Potassium and calcium changes in injured spinal cords. Brain Res, 365(1): 42–53

110 Zhang A L, Hao J X, Seiger A, Xu X J, Wiesenfeld-Hallin Z, Grant G, Aldskogius H (1994). Decreased GABA immunoreactivity in spinal cord dorsal horn neurons after transient spinal cord ischemia in the rat. Brain Res, 656(1): 187–190

111 Zhou Q, Anderson D J (2002). The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell, 109(1): 61–73