, Volume 6, Issue 2, pp 263–277 | Cite as

Embryonic stem cell-derived neural precursor grafts for treatment of temporal lobe epilepsy

  • Xu Maisano
  • Joseph Carpentino
  • Sandy Becker
  • Robert Lanza
  • Gloster Aaron
  • Laura Grabel
  • Janice R. Naegele
Theme 2: Cell Therapy


Complex partial seizures arising from mesial temporal lobe structures are a defining feature of mesial temporal lobe epilepsy (TLE). For many TLE patients, there is an initial traumatic head injury that is the precipitating cause of epilepsy. Severe TLE can be associated with neuropathological changes, including hippocampal sclerosis, neurodegeneration in the dentate gyrus, and extensive reorganization of hippocampal circuits. Learning disabilities and psychiatric conditions may also occur in patients with severe TLE for whom conventional anti-epileptic drugs are ineffective. Novel treatments are needed to limit or repair neuronal damage, particularly to hippocampus and related limbic regions in severe TLE and to suppress temporal lobe seizures. A promising therapeutic strategy may be to restore inhibition of dentate gyrus granule neurons by means of cell grafts of embryonic stem cell-derived GABAergic neuron precursors. “Proof-of-concept” studies show that human and mouse embryonic stem cell-derived neural precursors can survive, migrate, and integrate into the brains of rodents in different experimental models of TLE. In addition, studies have shown that hippocampal grafts of cell lines engineered to release GABA or other anticonvulsant molecules can suppress seizures. Furthermore, transplants of fetal GABAergic progenitors from the mouse or human brain have also been shown to suppress the development of seizures. Here, we review these relevant studies and highlight areas of future research directed toward producing embryonic stem cell-derived GABAergic interneurons for cell-based therapies for treating TLE.

Key Words

Seizures ES cell therapy hilus hippocampus GABA interneuron Sox1 GFP sonic hedgehog 


  1. 1.
    Mathern GW, Pretorius JK, Babb TL. Influence of the type of initial precipitating injury and at what age it occurs on course and outcome in patients with temporal lobe seizures. J Neurosurg 1995;82: 220–227.PubMedGoogle Scholar
  2. 2.
    Margerison JH, Corsellis JA. Epilepsy and the temporal lobes. A clinical, electroencephalographic and neuropathological study of the brain in epilepsy, with particular reference to the temporal lobes. Brain 1966;89: 499–530.PubMedGoogle Scholar
  3. 3.
    Schwartzkroin PA. Origins of the epileptic state. Epilepsia 1997; 38: 853–858.PubMedGoogle Scholar
  4. 4.
    Golarai G, Greenwood AC, Feeney DM, Connor JA. Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury. J Neurosci 2001;21: 8523–8537.PubMedGoogle Scholar
  5. 5.
    Ribak CE, Tran PH, Spigelman I, Okazaki MM, Nadler JV. Status epilepticus-induced hilar basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry. J Comp Neurol 2000;428: 240–253.PubMedGoogle Scholar
  6. 6.
    Ribak CE, Dashtipour K. Neuroplasticity in the damaged dentate gyms of the epileptic brain. Prog Brain Res 2002;136: 319–328.PubMedGoogle Scholar
  7. 7.
    Scharfman HE, Gray WP. Relevance of seizure-induced neurogenesis in animal models of epilepsy to the etiology of temporal lobe epilepsy. Epilepsia 2007;48(suppl 2): 33–41.PubMedGoogle Scholar
  8. 8.
    Loring DW, Marino S, Meador KJ. Neuropsychological and behavioral effects of antiepilepsy drugs. Neuropsychol Rev 2007; 17: 413–425.PubMedGoogle Scholar
  9. 9.
    Engel J, Jr. The timing of surgical intervention for mesial temporal lobe epilepsy: a plan for a randomized clinical trial. Arch Neurol 1999;56: 1338–1341.PubMedGoogle Scholar
  10. 10.
    Heller AC, Padilla RV, Mamelak AN. Complications of epilepsy surgery in the first 8 years after neurosurgical training. Surg Neurol 2008 May 29. [Epub ahead of print].Google Scholar
  11. 11.
    Neal EG, Chaffe H, Schwartz RH, et al. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 2008;7: 500–506.PubMedGoogle Scholar
  12. 12.
    Bumanglag AV, Sloviter RS. Minimal latency to hippocampal epileptogenesis and clinical epilepsy after perforant pathway stimulation-induced status epilepticus in awake rats. J Comp Neurol 2008;510: 561–580.PubMedGoogle Scholar
  13. 13.
    Choi YS, Lin SL, Lee B, et al. Status epilepticus-induced somatostatinergic hilar intemeuron degeneration is regulated by striatal enriched protein tyrosine phosphatase. J Neurosci 2007;27: 2999–3009.PubMedGoogle Scholar
  14. 14.
    Dinocourt C, Petanjek Z, Freund TF, Ben-Ari Y, Esclapez M. Loss of intemeurons innervating pyramidal cell dendrites and axon initial segments in the CA1 region of the hippocampus following pilocarpine-induced seizures. J Comp Neurol 2003; 459: 407–425.PubMedGoogle Scholar
  15. 15.
    Kobayashi M, Buckmaster PS. Reduced inhibition of dentate granule cells in a model of temporal lobe epilepsy. J Neurosci 2003;23: 2440–2452.PubMedGoogle Scholar
  16. 16.
    de Lanerolle NC, Kim JH, Robbins RJ, Spencer DD. Hippocampal intemeuron loss and plasticity in human temporal lobe epilepsy. Brain Res 1989;495: 387–395.PubMedGoogle Scholar
  17. 17.
    Buckmaster PS, Jongen-Relo AL. Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats. J Neurosci 1999;19: 9519–9529.PubMedGoogle Scholar
  18. 18.
    Buckmaster PS, Otero-Corchon V, Rubinstein M, Low MJ. Heightened seizure severity in somatostatin knockout mice. Epilepsy Res 2002;48: 43–56.PubMedGoogle Scholar
  19. 19.
    Freund TF, Buzsaki G. Interneurons of the hippocampus. Hippocampus 1996;6: 347–470.PubMedGoogle Scholar
  20. 20.
    Buckmaster PS, Yamawaki R, Zhang GF. Axon arbors and synaptic connections of a vulnerable population of intemeurons in the dentate gyrus in vivo. J Comp Neurol 2002;445: 360–373.PubMedGoogle Scholar
  21. 21.
    Vezzani A, Sperk G, Colmers WF. Neuropeptide Y: emerging evidence for a functional role in seizure modulation. Trends Neurosci 1999;22: 25–30.PubMedGoogle Scholar
  22. 22.
    Borges K, Gearing M, McDermott DL, et al. Neuronal and glial pathological changes during epileptogenesis in the mouse pilocarpine model. Exp Neurol 2003;182: 21–34.PubMedGoogle Scholar
  23. 23.
    Nishimura T, Schwarzer C, Gasser E, Kato N, Vezzani A, Sperk G. Altered expression of GABA(A) and GABA(B) receptor sub-unit mRNAs in the hippocampus after kindling and electrically induced status epilepticus. Neuroscience 2005;134: 691–704.PubMedGoogle Scholar
  24. 24.
    Laurén HB, Lopez-Picon FR, Korpi ER, Holopainen IE. Kainic acid-induced status epilepticus alters GABA receptor subunit mRNA and protein expression in the developing rat hippocampus. J Neurochem 2005;94: 1384–1394.PubMedGoogle Scholar
  25. 25.
    Sloviter RS, Zappone CA, Harvey BD, Bumanglag AV, Bender RA, Frotscher M. “Dormant basket cell” hypothesis revisited: relative vulnerabilities of dentate gyrus mossy cells and inhibitory intemeurons after hippocampal status epilepticus in the rat. J Comp Neurol 2003;459: 44–76.PubMedGoogle Scholar
  26. 26.
    Bekenstein JW, Lothman EW. Dormancy of inhibitory intemeurons in a model of temporal lobe epilepsy. Science 1993;259: 97–100.PubMedGoogle Scholar
  27. 27.
    Sloviter RS, Zappone CA, Harvey BD, Frotscher M. Kainic acid-induced recurrent mossy fiber innervation of dentate gyrus inhibitory intemeurons: possible anatomical substrate of granule cell hyper-inhibition in chronically epileptic rats. J Comp Neurol 2006;494: 944–960.PubMedGoogle Scholar
  28. 28.
    Leroy C, Poisbeau P, Keller AF, Nehlig A. Pharmacological plasticity of GABA(A) receptors at dentate gyrus synapses in a rat model of temporal lobe epilepsy. J Physiol 2004;557: 473–487.PubMedGoogle Scholar
  29. 29.
    Jiao Y, Nadler JV. Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy: correlation of cell loss with mossy fiber sprouting. Exp Neurol 2007;205: 569–582.PubMedGoogle Scholar
  30. 30.
    Tauck DL, Nadler JV. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats. J Neurosci 1985;5: 1016–1022.PubMedGoogle Scholar
  31. 31.
    Babb TL, Kupfer WR, Pretorius JK, Crandall PH, Levesque MF. Synaptic reorganization by mossy fibers in human epileptic fascia dentata. Neuroscience 1991;42: 351–363.PubMedGoogle Scholar
  32. 32.
    Gabriel S, Njunting M, Pomper JK, et al. Stimulus and potassium-induced epileptiform activity in the human dentate gyrus from patients with and without hippocampal sclerosis. J Neurosci 2004;24: 10416–10430.PubMedGoogle Scholar
  33. 33.
    Longo BM, Mello LE. Blockade of pilocarpine- or kainate-induced mossy fiber sprouting by cycloheximide does not prevent subsequent epileptogenesis in rats. Neurosci Lett 1997;226: 163–166.PubMedGoogle Scholar
  34. 34.
    Pitkanen A, Tuunanen J, Kalviainen R, Partanen K, Salmenpera T. Amygdala damage in experimental and human temporal lobe epilepsy. Epilepsy Res 1998;32: 233–253.PubMedGoogle Scholar
  35. 35.
    Jutila L, Ylinen A, Partanen K, et al. MR volumetry of the entorhinal, perirhinal, and temporopolar cortices in drug-refractory temporal lobe epilepsy. AJNR Am J Neuroradiol 2001;22: 1490–1501.PubMedGoogle Scholar
  36. 36.
    Hattiangady B, Rao MS, Shetty AK. Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus. Neurobiol Dis 2004;17: 473–490.PubMedGoogle Scholar
  37. 37.
    Doetsch F. The glial identity of neural stem cells. Nat Neurosci 2003;6: 1127–1134.PubMedGoogle Scholar
  38. 38.
    Schinder AF, Gage FH. A hypothesis about the role of adult neurogenesis in hippocampal function. Physiology (Bethesda) 2004;19: 253–261.Google Scholar
  39. 39.
    Carpentino JE, Hartman NW, Grabel LB, Naegele JR. Region-specific differentiation of embryonic stem cell-derived neural progenitor transplants into the adult mouse hippocampus following seizures. J Neurosci Res 2008;86: 512–524.PubMedGoogle Scholar
  40. 40.
    Kempermann G. They are not too excited: the possible role of adult-bom neurons in epilepsy. Neuron 2006;52: 935–937.PubMedGoogle Scholar
  41. 41.
    Steiner B, Zurborg S, Horster H, Fabel K, Kempermann G. Differential 24 h responsiveness of Prox1-expressing precursor cells in adult hippocampal neurogenesis to physical activity, environmental enrichment, and kainic acid-induced seizures. Neuroscience 2008;154: 521–529.PubMedGoogle Scholar
  42. 42.
    Jessberger S, Romer B, Babu H, Kempermann G. Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells. Exp Neurol 2005;196: 342–351.PubMedGoogle Scholar
  43. 43.
    Walter C, Murphy BL, Pun RY, Spieles-Engemann AL, Danzer SC. Pilocarpine-induced seizures cause selective time-dependent changes to adult-generated hippocampal dentate granule cells. J Neurosci 2007;27: 7541–552.PubMedGoogle Scholar
  44. 44.
    Loscher W, Gernert M, Heinemann U. Cell and gene therapies in epilepsy-promising avenues or blind alleys? Trends Neurosci 2008;31: 62–73.PubMedGoogle Scholar
  45. 45.
    Scheffler B, Edenhofer F, Brustle O. Merging fields: stem cells in neurogenesis, transplantation, and disease modeling. Brain Pathol 2006;16: 155–168.PubMedGoogle Scholar
  46. 46.
    Bjorklund A, Lindvall O. Cell replacement therapies for central nervous system disorders. Nat Neurosci 2000;3: 537–544.PubMedGoogle Scholar
  47. 47.
    Raedt R, Van Dycke A, Vonck K, Boon P. Cell therapy in models for temporal lobe epilepsy. Seizure 2007;16: 565–578.PubMedGoogle Scholar
  48. 48.
    Wichterle H, Garcia-Verdugo JM, Herrera DG, Alvarez-Buylla A. Young neurons from medial ganglionic eminence disperse in adult and embryonic brain. Nat Neurosci 1999;2: 461–466.PubMedGoogle Scholar
  49. 49.
    Alvarez-Dolado M, Calcagnotto ME, Karkar KM, et al. Cortical inhibition modified by embryonic neural precursors grafted into the postnatal brain. J Neurosci 2006;26: 7380–7389.PubMedGoogle Scholar
  50. 50.
    Detlev B. Cell and gene therapies for refractory epilepsy. Curr Neuropharmacol 2007;5: 115–125.PubMedGoogle Scholar
  51. 51.
    Buzsaki G, Ponomareff G, Bayardo F, Shaw T, Gage FH. Suppression and induction of epileptic activity by neuronal grafts. Proc Natl Acad Sci U S A 1988;85: 9327–9330.PubMedGoogle Scholar
  52. 52.
    Bengzon J, Kokaia Z, Lindvall O. Specific functions of grafted locus coeruleus neurons in the kindling model of epilepsy. Exp Neurol 1993;122: 143–154.PubMedGoogle Scholar
  53. 53.
    Shetty AK, Hattiangady B. Restoration of calbindin after fetal hippocampal CA3 cell grafting into the injured hippocampus in a rat model of temporal lobe epilepsy. Hippocampus 2007;17: 943–954.PubMedGoogle Scholar
  54. 54.
    Shetty AK, Turner DA. Fetal hippocampal cells grafted to kainate-lesioned CA3 region of adult hippocampus suppress aberrant supragranular sprouting of host mossy fibers. Exp Neurol 1997; 143: 231–245.PubMedGoogle Scholar
  55. 55.
    Loscher W, Ebert U, Lehmann H, Rosenthal C, Nikkhah G. Seizure suppression in kindling epilepsy by grafts of fetal GABAergic neurons in rat substantia nigra. J Neurosci Res 1998; 51: 196–209.PubMedGoogle Scholar
  56. 56.
    Chu K, Kim M, Jung KH, et al. Human neural stem cell transplantation reduces spontaneous recurrent seizures following pilocarpine-induced status epilepticus in adult rats. Brain Res 2004; 1023: 213–221.PubMedGoogle Scholar
  57. 57.
    Gernert M, Thompson KW, Loscher W, Tobin AJ. Genetically engineered GABA-producing cells demonstrate anticonvulsant effects and long-term transgene expression when transplanted into the central piriform cortex of rats. Exp Neurol 2002; 176: 183–192.PubMedGoogle Scholar
  58. 58.
    Thompson KW. Genetically engineered cells with regulatable GABA production can affect afterdischarges and behavioral seizures after transplantation into the dentate gyrus. Neuroscience 2005;133: 1029–1037.PubMedGoogle Scholar
  59. 59.
    Thompson KW, Suchomelova LM. Transplants of cells engineered to produce GABA suppress spontaneous seizures. Epilepsia 2004;45: 4–12.PubMedGoogle Scholar
  60. 60.
    Englund U, Bjorklund A, Wictorin K, Lindvall O, Kokaia M. Grafted neural stem cells develop into functional pyramidal neurons and integrate into host cortical circuitry. Proc Natl Acad Sci U S A 2002;99: 17089–17094.PubMedGoogle Scholar
  61. 61.
    Boison D. The adenosine kinase hypothesis of epileptogenesis. Prog Neurobiol 2008;84: 249–262.PubMedGoogle Scholar
  62. 62.
    Li T, Ren G, Lusardi T, et al. Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice. J Clin Invest 2008;118: 571–582.PubMedGoogle Scholar
  63. 63.
    Ren G, Li T, Lan JQ, Wilz A, Simon RP, Boison D. Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: a novel perspective for seizure control. Exp Neurol 2007;208: 26–37.PubMedGoogle Scholar
  64. 64.
    Shetty AK, Hattiangady B. Concise review: prospects of stem cell therapy for temporal lobe epilepsy. Stem Cells 2007;25: 2396–2407.PubMedGoogle Scholar
  65. 65.
    Li T, Steinbeck JA, Lusardi T, et al. Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants. Brain 2007;130: 1276–1288.PubMedGoogle Scholar
  66. 66.
    Fukuda H, Takahashi J, Watanabe K, et al. Fluorescence-activated cell sorting-based purification of embryonic stem cell-derived neural precursors averts tumor formation after transplantation. Stem Cells 2006;24: 763–771.PubMedGoogle Scholar
  67. 67.
    Cai C, Grabel L. Directing the differentiation of embryonic stem cells to neural stem cells. Dev Dyn 2007;236: 3255–3266.PubMedGoogle Scholar
  68. 68.
    Okabe S, Forsberg-Nilsson K, Spiro AC, Segal M, McKay RD. Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev 1996;59: 89–102.PubMedGoogle Scholar
  69. 69.
    Ying QL, Stavridis M, Griffiths D, Li M, Smith A. Conversion of embryonic stem cells into neuroectodermal precursors in adherent monoculture. Nat Biotechnol 2003;21: 183–186.PubMedGoogle Scholar
  70. 70.
    Bain G, Kitchens D, Yao M, Huettner JE, Gottlieb DI. Embryonic stem cells express neuronal properties in vitro. Dev Biol 1995; 168: 342–357.PubMedGoogle Scholar
  71. 71.
    Finley MF, Kulkami N, Huettner JE. Synapse formation and establishment of neuronal polarity by P19 embryonic carcinoma cells and embryonic stem cells. J Neurosci 1996;16: 1056–1065.PubMedGoogle Scholar
  72. 72.
    Strübing C, Ahnert-Hilger G, Shan J, Wiedenmann B, Hescheler J, Wobus AM. Differentiation of pluripotent embryonic stem cells into the neuronal lineage in vitro gives rise to mature inhibitory and excitatory neurons. Mech Dev 1995;53: 275–287.PubMedGoogle Scholar
  73. 73.
    Briistle O, Jones KN, Learish RD, et al. Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science 1999;285: 754–756.Google Scholar
  74. 74.
    Fraichard A, Chassande O, Bilbaut G, Dehay C, Savatier P, Samarut J. In vitro differentiation of embryonic stem cells into glial cells and functional neurons. J Cell Sci 1995;108(pt 10): 3181–3188.PubMedGoogle Scholar
  75. 75.
    Reubinoff BE, Itsykson P, Turetsky T, et al. Neural progenitors from human embryonic stem cells. Nat Biotechnol 2001;19: 1134–1140.PubMedGoogle Scholar
  76. 76.
    Zhang SC. Neural subtype specification from embryonic stem cells. Brain Pathol 2006;16: 132–142.PubMedGoogle Scholar
  77. 77.
    Gaspard N, Bouschet T, Hourez R, et al. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature 2008;455: 351–357.PubMedGoogle Scholar
  78. 78.
    Eiraku M, Watanabe K, Matsuo-Takasaki M, et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 2008;3: 519–532.PubMedGoogle Scholar
  79. 79.
    Goetz AK, Scheffler B, Chen HX, et al. Temporally restricted substrate interactions direct fate and specification of neural precursors derived from embryonic stem cells. Proc Natl Acad Sci U S A 2006;103: 11063–11068.PubMedGoogle Scholar
  80. 80.
    Wernig M, Benninger F, Schmandt T, et al. Functional integration of embryonic stem cell-derived neurons in vivo. J Neurosci 2004; 24: 5258–5268.PubMedGoogle Scholar
  81. 81.
    Zhang SC, Wernig M, Duncan ID, Brustle O, Thomson JA. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol 2001;19: 1129–1133.PubMedGoogle Scholar
  82. 82.
    Wichterle H, Lieberam I, Porter JA, Jessell TM. Directed differentiation of embryonic stem cells into motor neurons. Cell 2002; 110: 385–397.PubMedGoogle Scholar
  83. 83.
    Ruschenschmidt C, Koch PG, Brustle O, Beck H. Functional properties of ES cell-derived neurons engrafted into the hippocampus of adult normal and chronically epileptic rats. Epilepsia 2005;46(suppl 5): 174–183.PubMedGoogle Scholar
  84. 84.
    Watanabe K, Kamiya D, Nishiyama A, et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat Neurosci 2005;8: 288–296.PubMedGoogle Scholar
  85. 85.
    Barberi T, Klivenyi P, Calingasan NY, et al. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat Biotechnol 2003; 21: 1200–1207.PubMedGoogle Scholar
  86. 86.
    Zeng J, Du J, Zhao Y, Palanisamy N, Wang S. Baculoviral vector-mediated transient and stable transgene expression in human embryonic stem cells. Stem Cells 2007;25: 1055–1061.PubMedGoogle Scholar
  87. 87.
    Hamaguchi I, Woods NB, Panagopoulos I, et al. Lentivirus vector gene expression during ES cell-derived hematopoietic development in vitro. J Virol 2000;74: 10778–10784.PubMedGoogle Scholar
  88. 88.
    Oka M, Chang LJ, Costantini F, Terada N. Lentiviral vector-mediated gene transfer in embryonic stem cells. Methods Mol Biol 2006;329: 273–281.PubMedGoogle Scholar
  89. 89.
    Gropp M, Reubinoff B. Lentiviral vector-mediated gene delivery into human embryonic stem cells. Methods Enzymol 2006;420: 64–81.PubMedGoogle Scholar
  90. 90.
    Giudice A, Trounson A. Genetic modification of human embryonic stem cells for derivation of target cells. Cell Stem Cell 2008;2: 422–433.PubMedGoogle Scholar
  91. 91.
    Eiges R, Schuldiner M, Drukker M, Yanuka O, Itskovitz-Eldor J, Benvenisty N. Establishment of human embryonic stem cell-transfected clones carrying a marker for undifferentiated cells. Curr Biol 2001;11: 514–518.PubMedGoogle Scholar
  92. 92.
    Liew CG, Draper JS, Walsh J, Moore H, Andrews PW. Transient and stable transgene expression in human embryonic stem cells. Stem Cells 2007;25: 1521–1528.PubMedGoogle Scholar
  93. 93.
    Vallier L, Rugg-Gunn PJ, Bouhon IA, Andersson FK, Sadler AJ, Pedersen RA, et al. Enhancing and diminishing gene function in human embryonic stem cells. Stem Cells 2004;22: 2–11.PubMedGoogle Scholar
  94. 94.
    Siemen H, Nolden L, Terstegge S, Koch P, Brustle O. Nucleofection of human embryonic stem cells. Methods Mol Biol 2008; 423: 131–138.PubMedGoogle Scholar
  95. 95.
    Li M, Pevny L, Lovell-Badge R, Smith A. Generation of purified neural precursors from embryonic stem cells by lineage selection. Curr Biol 1998;8: 971–974.PubMedGoogle Scholar
  96. 96.
    Westmoreland JJ, Hancock CR, Condie BG. Neuronal development of embryonic stem cells: a model of GABAergic neuron differentiation. Biochem Biophys Res Commun 2001;284: 674–680.PubMedGoogle Scholar
  97. 97.
    Gupta A, Wang Y, Markram H. Organizing principles for a diversity of GABAergic intemeurons and synapses in the neocortex. Science 2000;287: 273–278.PubMedGoogle Scholar
  98. 98.
    Anderson SA, Kaznowski CE, Horn C, Rubenstein JL, McConnell SK. Distinct origins of neocortical projection neurons and inter-neurons in vivo. Cereb Cortex 2002;12: 702–709.PubMedGoogle Scholar
  99. 99.
    Anderson SA, Marin O, Horn C, Jennings K, Rubenstein JL. Distinct cortical migrations from the medial and lateral ganglionic eminences. Development 2001;128: 353–363.PubMedGoogle Scholar
  100. 100.
    Wichterle H, Tumbull DH, Nery S, Fishell G, Alvarez-Buylla A. In utero fate mapping reveals distinct migratory pathways and fates of neurons bom in the mammalian basal forebrain. Development 2001;128: 3759–3771.PubMedGoogle Scholar
  101. 101.
    Marin O, Anderson SA, Rubenstein JL. Origin and molecular specification of striatal intemeurons. J Neurosci 2000;20: 6063–6076.PubMedGoogle Scholar
  102. 102.
    Butt SJ, Cobos I, Golden J, Kessaris N, Pachnis V, Anderson S. Transcriptional regulation of cortical intemeuron development. J Neurosci 2007;27: 11847–11850.PubMedGoogle Scholar
  103. 103.
    Butt SJ, Fuccillo M, Nery S, et al. The temporal and spatial origins of cortical intemeurons predict their physiological subtype. Neuron 2005;48: 591–604.PubMedGoogle Scholar
  104. 104.
    Wonders CP, Taylor L, Welagen J, Mbata IC, Xiang JZ, Anderson SA. A spatial bias for the origins of intemeuron subgroups within the medial ganglionic eminence. Dev Biol 2008;314: 127–136.PubMedGoogle Scholar
  105. 105.
    Flames N, Pla R, Gelman DM, Rubenstein JL, Puelles L, Marín O. Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcriptional codes. J Neurosci 2007;27: 9682–9695.PubMedGoogle Scholar
  106. 106.
    Zhao Y, Flandin P, Long JE, Cuesta MD, Westphal H, Rubenstein JL. Distinct molecular pathways for development of telencephalic intemeuron subtypes revealed through analysis of Lhx6 mutants. J Comp Neurol 2008;510: 79–99.PubMedGoogle Scholar
  107. 107.
    Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8 is involved in the determination of cholinergic or GABAergic cell fate. J Neurochem 2005;94: 723–730.PubMedGoogle Scholar
  108. 108.
    Manabe T, Tatsumi K, Inoue M, et al. L3/Lhx8 is a pivotal factor for cholinergic differentiation of murine embryonic stem cells. Cell Death Differ 2007;14: 1080–1085.PubMedGoogle Scholar
  109. 109.
    Yun K, Fischman S, Johnson J, Hrabe de Angelis M, Weinmaster G, Rubenstein JL. Modulation of the notch signaling by Mash1 and Dlx1/2 regulates sequential specification and differentiation of progenitor cell types in the subcortical telencephalon. Development 2002;129: 5029–5040.PubMedGoogle Scholar
  110. 110.
    Casarosa S, Fode C, Guillemot F. Mash1 regulates neurogenesis in the ventral telencephalon. Development 1999;126: 525–534.PubMedGoogle Scholar
  111. 111.
    Wang JM, Johnston PB, Ball BG, Brinton RD. The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J Neurosci 2005;25: 4706–4718.PubMedGoogle Scholar
  112. 112.
    Li H, Radford JC, Ragusa MJ, et al. Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci U S A 2008;105: 9397–9402.PubMedGoogle Scholar
  113. 113.
    Bemreuther C, Dihné M, Johann V, et al. Neural cell adhesion molecule L1-transfected embryonic stem cells promote functional recovery after excitotoxic lesion of the mouse striatum. J Neurosci 2006;26: 11532–11539.Google Scholar
  114. 114.
    Passier R, Oostwaard DW, Snapper J, et al. Increased cardiomyocyte differentiation from human embryonic stem cells in serum-free cultures. Stem Cells 2005;23: 772–780.PubMedGoogle Scholar
  115. 115.
    Denham M, Cole TJ, Mollard R. Embryonic stem cells form glandular structures and express surfactant protein C following culture with dissociated fetal respiratory tissue. Am J Physiol Lung Cell Mol Physiol 2006;290: L1210-L1215.PubMedGoogle Scholar
  116. 116.
    Trinh HH, Reid J, Shin E, Liapi A, Pamavelas JG, Nadarajah B. Secreted factors from ventral telencephalon induce the differentiation of GABAergic neurons in cortical cultures. Eur J Neurosci 2006;24: 2967–2977.PubMedGoogle Scholar
  117. 117.
    Yao S, Chen S, Clark J, et al. Long-term self-renewal and directed differentiation of human embryonic stem cells in chemically defined conditions. Proc Natl Acad Sci U S A 2006;103: 6907–6912.PubMedGoogle Scholar
  118. 118.
    Ding S, Schultz PG. A role for chemistry in stem cell biology. Nat Biotechnol 2004;22: 833–840.PubMedGoogle Scholar
  119. 119.
    Sartipy P, Strehl R, Bjorquist P, Hyllner J. Low molecular weight compounds for in vitro fate determination of human embryonic stem cells. Pharmacol Res 2008;58: 152–157.PubMedGoogle Scholar
  120. 120.
    Takahashi T, Lord B, Schulze PC, et al. Ascorbic acid enhances differentiation of embryonic stem cells into cardiac myocytes. Circulation 2003;107: 1912–1916.PubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2009

Authors and Affiliations

  • Xu Maisano
    • 1
  • Joseph Carpentino
    • 2
  • Sandy Becker
    • 3
  • Robert Lanza
    • 3
  • Gloster Aaron
    • 1
  • Laura Grabel
    • 1
  • Janice R. Naegele
    • 1
    • 4
  1. 1.Program in Neuroscience and Behavior, Department of BiologyWesleyan UniversityMiddletown
  2. 2.Program in Stem Cell Biology and Regenerative Medicine, McKnight Brain InstituteUniversity of FloridaGainesville
  3. 3.Advanced Cell Technology, Inc.Worcester
  4. 4.Department of Biology, Hall-Atwater LaboratoryWesleyan UniversityMiddletown

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