PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of neurotherwww.springer.comThis journalToc AlertsSubmit OnlineOpen Choice
 
Neurotherapeutics. 2009 April; 6(2): 263–277.
PMCID: PMC2830617
NIHMSID: NIHMS167669

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

Summary

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

References

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. [PubMed]
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. [PubMed]
3. Schwartzkroin PA. Origins of the epileptic state. Epilepsia. 1997;38:853–858. [PubMed]
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. [PubMed]
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. [PubMed]
6. Ribak CE, Dashtipour K. Neuroplasticity in the damaged dentate gyms of the epileptic brain. Prog Brain Res. 2002;136:319–328. [PubMed]
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. [PMC free article] [PubMed]
8. Loring DW, Marino S, Meador KJ. Neuropsychological and behavioral effects of antiepilepsy drugs. Neuropsychol Rev. 2007;17:413–425. [PubMed]
9. Engel J. The timing of surgical intervention for mesial temporal lobe epilepsy: a plan for a randomized clinical trial. Arch Neurol. 1999;56:1338–1341. [PubMed]
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]. [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
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. [PMC free article] [PubMed]
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. [PubMed]
15. Kobayashi M, Buckmaster PS. Reduced inhibition of dentate granule cells in a model of temporal lobe epilepsy. J Neurosci. 2003;23:2440–2452. [PubMed]
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. [PubMed]
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. [PubMed]
18. Buckmaster PS, Otero-Corchon V, Rubinstein M, Low MJ. Heightened seizure severity in somatostatin knockout mice. Epilepsy Res. 2002;48:43–56. [PubMed]
19. Freund TF, Buzsaki G. Interneurons of the hippocampus. Hippocampus. 1996;6:347–470. [PubMed]
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. [PubMed]
21. Vezzani A, Sperk G, Colmers WF. Neuropeptide Y: emerging evidence for a functional role in seizure modulation. Trends Neurosci. 1999;22:25–30. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
26. Bekenstein JW, Lothman EW. Dormancy of inhibitory intemeurons in a model of temporal lobe epilepsy. Science. 1993;259:97–100. [PubMed]
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. [PMC free article] [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
37. Doetsch F. The glial identity of neural stem cells. Nat Neurosci. 2003;6:1127–1134. [PubMed]
38. Schinder AF, Gage FH. A hypothesis about the role of adult neurogenesis in hippocampal function. Physiology (Bethesda) 2004;19:253–261. [PubMed]
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. [PubMed]
40. Kempermann G. They are not too excited: the possible role of adult-bom neurons in epilepsy. Neuron. 2006;52:935–937. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
44. Loscher W, Gernert M, Heinemann U. Cell and gene therapies in epilepsy-promising avenues or blind alleys? Trends Neurosci. 2008;31:62–73. [PubMed]
45. Scheffler B, Edenhofer F, Brustle O. Merging fields: stem cells in neurogenesis, transplantation, and disease modeling. Brain Pathol. 2006;16:155–168. [PubMed]
46. Bjorklund A, Lindvall O. Cell replacement therapies for central nervous system disorders. Nat Neurosci. 2000;3:537–544. [PubMed]
47. Raedt R, Van Dycke A, Vonck K, Boon P. Cell therapy in models for temporal lobe epilepsy. Seizure. 2007;16:565–578. [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
50. Detlev B. Cell and gene therapies for refractory epilepsy. Curr Neuropharmacol. 2007;5:115–125. [PMC free article] [PubMed]
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. [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
59. Thompson KW, Suchomelova LM. Transplants of cells engineered to produce GABA suppress spontaneous seizures. Epilepsia. 2004;45:4–12. [PubMed]
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. [PubMed]
61. Boison D. The adenosine kinase hypothesis of epileptogenesis. Prog Neurobiol. 2008;84:249–262. [PMC free article] [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
64. Shetty AK, Hattiangady B. Concise review: prospects of stem cell therapy for temporal lobe epilepsy. Stem Cells. 2007;25:2396–2407. [PMC free article] [PubMed]
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. [PubMed]
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. [PubMed]
67. Cai C, Grabel L. Directing the differentiation of embryonic stem cells to neural stem cells. Dev Dyn. 2007;236:3255–3266. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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;108:3181–3188. [PubMed]
75. Reubinoff BE, Itsykson P, Turetsky T, et al. Neural progenitors from human embryonic stem cells. Nat Biotechnol. 2001;19:1134–1140. [PubMed]
76. Zhang SC. Neural subtype specification from embryonic stem cells. Brain Pathol. 2006;16:132–142. [PubMed]
77. Gaspard N, Bouschet T, Hourez R, et al. An intrinsic mechanism of corticogenesis from embryonic stem cells. Nature. 2008;455:351–357. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
82. Wichterle H, Lieberam I, Porter JA, Jessell TM. Directed differentiation of embryonic stem cells into motor neurons. Cell. 2002;110:385–397. [PubMed]
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. [PubMed]
84. Watanabe K, Kamiya D, Nishiyama A, et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat Neurosci. 2005;8:288–296. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
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. [PubMed]
89. Gropp M, Reubinoff B. Lentiviral vector-mediated gene delivery into human embryonic stem cells. Methods Enzymol. 2006;420:64–81. [PubMed]
90. Giudice A, Trounson A. Genetic modification of human embryonic stem cells for derivation of target cells. Cell Stem Cell. 2008;2:422–433. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
94. Siemen H, Nolden L, Terstegge S, Koch P, Brustle O. Nucleofection of human embryonic stem cells. Methods Mol Biol. 2008;423:131–138. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
101. Marin O, Anderson SA, Rubenstein JL. Origin and molecular specification of striatal intemeurons. J Neurosci. 2000;20:6063–6076. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PMC free article] [PubMed]
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. [PMC free article] [PubMed]
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. [PMC free article] [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
110. Casarosa S, Fode C, Guillemot F. Mash1 regulates neurogenesis in the ventral telencephalon. Development. 1999;126:525–534. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
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. [PubMed]
118. Ding S, Schultz PG. A role for chemistry in stem cell biology. Nat Biotechnol. 2004;22:833–840. [PubMed]
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. [PubMed]
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. [PubMed]

Articles from Neurotherapeutics are provided here courtesy of Springer