Protocols for Generating ES Cell-Derived Dopamine Neurons

  • Sonja KriksEmail author
  • Lorenz Studer
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 651)


Stem cells are defined by their ability to self-renew and to differentiate into specific specialized cell types. Pluripotent stem cells such as embryonic stem cells are capable of differentiating into all cell types of the three germ layers. Self-renewal and differentiation potential are properties that make stem cells an attractive source for cell therapeutic efforts including the treatment of neurological diseases such as Parkinson’s disease (PD). Parkinson’s disease is one of the most common neurological disorders and is characterized by the selective degeneration of dopamine (DA) neurons in the ventral midbrain. The midbrain region contains three groups of DA neurons, the retrorubral field (A8), the tegmental area of the ventral midbrain (VTA, A10) and the substantia nigra pars compacta (A9). Only the latter subgroup is primarily affected in PD and responsible for most of the motor dysfunction. Due to this rather selective loss of DA neurons in the substantia nigra, PD is considered a neurological disease amenable to cell replacement. Cell replacement therapy in PD has been attempted in several hundred patients worldwide using fetal human DA neurons. While promising results have been reported in several open label studies (e.g., 1,2) placebo-controlled clinical trials using human fetal dopamine neurons have yielded modest clinical improvement at best.3,4 Furthermore, a subset of these patients displayed disabling graft-induced dyskinesias. There are many potential reasons for this relatively poor outcome as discussed in detail elsewhere.5 However, the limited availability of donor tissue, the low percentage of DA neurons within fetal grafts and ethical concerns associated with the use of human fetal tissue suggest that alternative cell sources are required for successful clinical translation.


Embryonic Stem Cell Dopaminergic Neuron Human Embryonic Stem Cell Dopamine Neuron Mouse Embryonic Stem Cell 
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  1. 1.
    Piccini P, Brooks DJ, Bjorklund A et al. Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nature Neuroscience 1999; 2:1137–1140.CrossRefPubMedGoogle Scholar
  2. 2.
    Lindvall O, Brundin P, Widner H et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 1990; 247:574–577.CrossRefPubMedGoogle Scholar
  3. 3.
    Freed CR, Greene PE, Breeze RE et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001; 344:710–719.CrossRefPubMedGoogle Scholar
  4. 4.
    Olanow CW, Goetz CG, Kordower JH et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 2003; 54:403–414.CrossRefPubMedGoogle Scholar
  5. 5.
    Bjorklund A, Dunnett SB, Brundin P et al. Neural transplantation for the treatment of Parkinson’s disease. Lancet Neurol 2003; 2:437–445.CrossRefPubMedGoogle Scholar
  6. 6.
    Smith WC, Harland RM. Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos. Cell 1992; 70:829–840.CrossRefPubMedGoogle Scholar
  7. 7.
    Sasai Y, Lu B, Steinbeisser H et al. Regulation of neural induction by the Chd and Bmp-4 antagonistic patterning signals in Xenopus. Nature 1995; 377:757.CrossRefPubMedGoogle Scholar
  8. 8.
    Hemmati Brivanlou A, Kelly OG, Melton DA. Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity. Cell 1994; 77:283–295.CrossRefPubMedGoogle Scholar
  9. 9.
    Cox WG, Hemmati-Brivanlou A. Caudalization of neural fate by tissue recombination and bFGF. Development 1995; 121:4349–4358.PubMedGoogle Scholar
  10. 10.
    Doniach T. Basic FGF as an inducer of anteroposterior neural pattern. Cell 1995; 83:1067–1070.CrossRefPubMedGoogle Scholar
  11. 11.
    McGrew LL, Lai CJ, Moon RT. Specification of the anteroposterior neural axis through synergistic interaction of the Wnt signaling cascade with noggin and follistatin. Dev Biol 1995; 172:337–342.CrossRefPubMedGoogle Scholar
  12. 12.
    Bang AG, Papalopulu N, Kintner C et al. Expression of Pax-3 is initiated in the early neural plate by posteriorizing signals produced by the organizer and by posterior non-axial mesoderm. Development 1997; 124:2075–2085.PubMedGoogle Scholar
  13. 13.
    Blumberg B, Bolado J Jr, Moreno TA et al. An essential role for retinoid signaling in anteroposterior neural patterning. Development 1997; 124:373–379.PubMedGoogle Scholar
  14. 14.
    Crossley PH, Martinez S, Martin GR. Midbrain development induced by FGF8 in the chick embryo. Nature 1996; 380:66–68.CrossRefPubMedGoogle Scholar
  15. 15.
    Hynes M, Porter JA, Chiang C et al. Induction of midbrain dopaminergic neurons by sonic hedgehog. Neuron 1995; 15:35–44.CrossRefPubMedGoogle Scholar
  16. 16.
    Ye WL, Shimamura K, Rubenstein JR et al. FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 1998; 93:755–766.CrossRefPubMedGoogle Scholar
  17. 17.
    Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981; 292:154–156.CrossRefPubMedGoogle Scholar
  18. 18.
    Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 1981; 78:7634–7638.CrossRefPubMedGoogle Scholar
  19. 19.
    Thomas KR, Capecchi MR. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 1987; 51:503–512.CrossRefPubMedGoogle Scholar
  20. 20.
    Doetschman T, Gregg RG, Maeda N et al. Targetted correction of a mutant HPRT gene in mouse embryonic stem cells. Nature 1987; 330:576–578.CrossRefPubMedGoogle Scholar
  21. 21.
    Ying QL, Nichols J, Chambers I et al. BMP induction of id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3. Cell 2003; 115:281–292.CrossRefPubMedGoogle Scholar
  22. 22.
    Ying QL, Wray J, Nichols J et al. The ground state of embryonic stem cell self-renewal. Nature 2008; 453:519–523.CrossRefPubMedGoogle Scholar
  23. 23.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS et al. Embryonic stem cell lines derived from human blastocysts. Science 1998; 282:1145–1147.CrossRefPubMedGoogle Scholar
  24. 24.
    Reubinoff BE, Pera MF, Fong CY et al. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 2000; 18:399–404.CrossRefPubMedGoogle Scholar
  25. 25.
    Xu CH, Inokuma MS, Denham J et al. Feeder-free growth of undifferentiated human embryonic stem cells. Nature Biotechnology 2001; 19:971–974.CrossRefPubMedGoogle Scholar
  26. 26.
    Nichols J, Chambers I, Taga T et al. Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines. Development 2001; 128:2333–2339.PubMedGoogle Scholar
  27. 27.
    Amit M, Shariki C, Margulets V et al. Feeder layer and serum-free culture of human embryonic stem cells. Biol Reprod 2004; 70:837–845.CrossRefPubMedGoogle Scholar
  28. 28.
    Vallier L, Reynolds D, Pedersen RA. Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Dev Biol 2004; 275:403–421.CrossRefPubMedGoogle Scholar
  29. 29.
    Pera MF, Andrade J, Houssami S et al. Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist noggin. J Cell Sci 2004; 117:1269–1280.CrossRefPubMedGoogle Scholar
  30. 30.
    Xu RH, Chen X, Li DS et al. BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nat Biotechnol 2002; 20:1261–1264.CrossRefPubMedGoogle Scholar
  31. 31.
    Tesar PJ, Chenoweth JG, Brook FA et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 2007; 448:196–199.CrossRefPubMedGoogle Scholar
  32. 32.
    Brons IG, Smithers LE, Trotter MW et al. Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 2007; 448:191–195.CrossRefPubMedGoogle Scholar
  33. 33.
    Lensch MW, Schlaeger TM, Zon LI et al. Teratoma formation assays with human embryonic stem cells: a rationale for one type of human-animal chimera. Cell Stem Cell 2007; 1:253–258.CrossRefPubMedGoogle Scholar
  34. 34.
    Ferri AL, Lin W, Mavromatakis YE et al. Foxal and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development 2007; 134:2761–2769.CrossRefPubMedGoogle Scholar
  35. 35.
    Kittappa R, Chang WW, Awatramani RB et al. The foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age. PLoS Biol 2007; 5:e325.CrossRefPubMedGoogle Scholar
  36. 36.
    Zetterström RH, Solomin L, Jansson L et al. Dopamine neuron agenesis in Nurr1-deficient mice. Science 1997; 276:248–250.CrossRefPubMedGoogle Scholar
  37. 37.
    Smidt MP, Van Schaick HA, Lanctot C et al. A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc Natl Acad Sci USA 1997; 94:13305–13310.CrossRefPubMedGoogle Scholar
  38. 38.
    Andersson E, Tryggvason U, Deng Q et al. Identification of intrinsic determinants of midbrain dopamine neurons. Cell 2006; 124:393–405.CrossRefPubMedGoogle Scholar
  39. 39.
    Vernay B, Koch M, Vaccarino F et al. Otx2 regulates subtype specification and neurogenesis in the midbrain. J Neurosci 2005; 25:4856–4867.CrossRefPubMedGoogle Scholar
  40. 40.
    Smidt MP, Asbreuk CH, Cox JJ et al. A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat Neurosci 2000; 3:337–341.CrossRefPubMedGoogle Scholar
  41. 41.
    Ohyama K, Ellis P, Kimura S et al. Directed differentiation of neural cells to hypothalamic dopaminergic neurons. Development 2005; 132:5185–5197.CrossRefPubMedGoogle Scholar
  42. 42.
    Grace AA, Onn SP. Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro. J Neurosci 1989; 9:3463–3481.PubMedGoogle Scholar
  43. 43.
    Nirenberg MJ, Vaughan RA, Uhl GR et al. The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons. J Neurosci 1996; 16:436–447.PubMedGoogle Scholar
  44. 44.
    Sesack SR, Aoki C, Pickel VM. Ultrastructural localization of D2 receptor-like immunoreactivity in midbrain dopamine neurons and their striatal targets. J Neurosci 1994; 14:88–106.PubMedGoogle Scholar
  45. 45.
    Kim JH, Auerbach JM, Rodriguez-Gomez JA et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 2002; 418:50–56.CrossRefPubMedGoogle Scholar
  46. 46.
    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.CrossRefPubMedGoogle Scholar
  47. 47.
    Perrier AL, Tabar V, Barberi T et al. From the cover: Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA 2004; 101:12543–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Yan Y, Yang D, Zarnowska ED et al. Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells 2005; 23:781–790.CrossRefPubMedGoogle Scholar
  49. 49.
    Lee SH, Lumelsky N, Studer L et al. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 2000; 18:675–679.CrossRefPubMedGoogle Scholar
  50. 50.
    Perrier AL, Tabar V, Barberi T et al. Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA 2004; 101:12543–12548.CrossRefPubMedGoogle Scholar
  51. 51.
    Rodriguez-Gomez JA, Lu JQ, Velasco I et al. Persistent dopamine functions of neurons derived from embryonic stem cells in a rodent model of Parkinson disease. Stem Cells 2007; 25:918–928.CrossRefPubMedGoogle Scholar
  52. 52.
    Doetschman TC, Eistetter H, Katz M et al. The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium. J Embryol Exp Morphol 1985; 87:27–45.PubMedGoogle Scholar
  53. 53.
    Bain G, Kitchens D, Yao M et al. Embryonic stem cells express neuronal properties in vitro. Dev Biol 1995; 168:342–357.CrossRefPubMedGoogle Scholar
  54. 54.
    Okabe S, Forsberg-Nilsson K, Spiro AC et al. Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev 1996; 59:89–102.CrossRefPubMedGoogle Scholar
  55. 55.
    Zhang SC, Wernig M, Duncan ID et al. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat Biotechnol 2001; 19:1129–1133.CrossRefPubMedGoogle Scholar
  56. 56.
    Carpenter MK, Inokuma MS, Denham J et al. Enrichment of neurons and neural precursors from human embryonic stem cells. Exp Neurol 2001; 172:383–397.CrossRefPubMedGoogle Scholar
  57. 57.
    Yang D, Zhang ZJ, Oldenburg M et al. Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in parkinsonian rats. Stem Cells 2008; 26:55–63.CrossRefPubMedGoogle Scholar
  58. 58.
    Roy NS, Cleren C, Singh SK et al. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nature Med 2006; 12:1259–1268.CrossRefPubMedGoogle Scholar
  59. 59.
    Kawasaki H, Mizuseki, Nishikawa S et al. Induction of midbrain dopaminergic neurons from es cells by stromal cell—derived inducing activity. Neuron 2000; 28:31–40.CrossRefPubMedGoogle Scholar
  60. 60.
    Morizane A, Takahashi J, Shinoyama M et al. Generation of graftable dopaminergic neuron progenitors from mouse ES cells by a combination of coculture and neurosphere methods. J Neurosci Res 2006; 83:1015–1027.CrossRefPubMedGoogle Scholar
  61. 61.
    Tabar V, Tomishima M, Panagiotakos G et al. Therapeutic cloning in individual Parkinsonian mice. Nature Med 2008; 14:379–381.CrossRefPubMedGoogle Scholar
  62. 62.
    Kawasaki H, Suernori H, Mizuseki K et al. Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity. Proc Natl Acad Sci USA 2002; 99:1580–1585.CrossRefPubMedGoogle Scholar
  63. 63.
    Mizuseki K, Sakamoto T, Watanabe K et al. Generation of neural crest-derived peripheral neurons and floor plate cells from mouse and primate embryonic stem cells. Proc Natl Acad Sci USA 2003; 100:5828–5833.CrossRefPubMedGoogle Scholar
  64. 64.
    Elkabetz Y, Panagiotakos G, AlShamy G et al. Human ES cell-derived neural rosettes reveal a functionally dinstinct early neural stem cell stage. Genes Dev 2008; 22:152–165.CrossRefPubMedGoogle Scholar
  65. 65.
    Speamann H, Mangold H. Induktion von embryonanlagen durch implantation artfremder organisatoren. Wilhelm Roux Arch Entw Mech Organ 1924; 100:599–638.Google Scholar
  66. 66.
    Reubinoff BE, Itsykson P, Turetsky T et al. Neural progenitors from human embryonic stem cells. Nat Biotechnol 2001; 19:1134–1140.CrossRefPubMedGoogle Scholar
  67. 67.
    Tropepe V, Hitoshi S, Sirard C et al. Direct neural fate specification from embryonic stem cells: A primitive mammalian neural stem cell stage acquired through a default mechanism. Neuron 2001; 30:65–78.CrossRefPubMedGoogle Scholar
  68. 68.
    Smukler SR, Runciman SB, Xu S et al. Embryonic stem cells assume a primitive neural stem cell fate in the absence of extrinsic influences. J Cell Biol 2006; 172:79–90.CrossRefPubMedGoogle Scholar
  69. 69.
    Conti L, Pollard SM, Gorba T et al. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol 2005; 3:e283.CrossRefPubMedGoogle Scholar
  70. 70.
    Itsykson P, Ilouz N, Turetsky T et al. Derivation of neural precursors from human embryonic stem cells in the presence of noggin. Mol Cell Neurosci 2005; 30:24–36.CrossRefPubMedGoogle Scholar
  71. 71.
    Sonntag KC, Pruszak J, Yoshizaki T et al. Enhanced yield of neuroepithelial precursors and midbrain-like dopaminergic neurons from human embryonic stem cells using the BMP antagonist noggin. Stem Cells 2007; 25:411–418.CrossRefPubMedGoogle Scholar
  72. 72.
    Watanabe K, Kamiya D, Nishiyama A et al. Directed differentiation of telencephalic precursors from embryonic stem cells. Nat Neurosci 2005; 8:288–296.CrossRefPubMedGoogle Scholar
  73. 73.
    Watanabe K, Ueno M, Kamiya D et al. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat Biotechnol 2007; 25:681–686.CrossRefPubMedGoogle Scholar
  74. 74.
    Ferrari D, Sanchez-Pernaute R, Lee H et al. Transplanted dopamine neurons derived from primate ES cells preferentially innervate DARPP-32 striatal progenitors within the graft. Eur J Neurosci 2006; 24:1885–1896.CrossRefPubMedGoogle Scholar
  75. 75.
    Sanchez-Pernaute R, Studer L, Ferrari D et al. Long-term survival of dopamine neurons derived from parthenogenetic primate embryonic stem cells (Cyno1) in rat and primate striatum. Stem Cells 2005; 23:914–922.CrossRefPubMedGoogle Scholar
  76. 76.
    Chung S, Sonntag KC, Andersson T et al. Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neurons. Eur J Neurosci 2002; 16:1829–1838.CrossRefPubMedGoogle Scholar
  77. 77.
    Martinat C, Bacci JJ, Leete T et al. Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proc Natl Acad Sci USA 2006; 103:2874–2879.CrossRefPubMedGoogle Scholar
  78. 78.
    Park CH, Minn YK, Lee JY et al. In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J Neurochem 2005; 92:1265–1276.CrossRefPubMedGoogle Scholar
  79. 79.
    Ben-Hur T, Idelson M, Khaner H et al. Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats. Stem Cells 2004; 22:1246–1255.CrossRefPubMedGoogle Scholar
  80. 80.
    Brederlau A, Correia AS, Anisimov SV et al. Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells 2006; 24:1433–1440.CrossRefPubMedGoogle Scholar
  81. 81.
    Tabar V, Panagiotakos G, Greenberg ED et al. Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain. Nat Biotechnol 2005; 23:601–606.CrossRefPubMedGoogle Scholar
  82. 82.
    Sgado P, Alberi L, Gherbassi D et al. Slow progressive degeneration of nigral dopaminergic neurons in postnatal engrailed mutant mice. Proc Natl Acad Sci USA 2006; 103:15242–15247.CrossRefPubMedGoogle Scholar
  83. 83.
    Saucedo-Cardenas O, Quintana-Hau JD, Le WD et al. Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc Natl Acad Sci USA 1998; 95:4013–4018.CrossRefPubMedGoogle Scholar
  84. 84.
    Ko JY, Park CH, Koh HC et al. Human embryonic stem cell-derived neural precursors as a continuous, stable and on-demand source for human dopamine neurons. J Neurochem 2007; 103:1417–1429.CrossRefPubMedGoogle Scholar
  85. 85.
    Hong S, Kang UJ, Isacson O et al. Neural precursors derived from human embryonic stem cells maintain long-term proliferation without losing the potential to differentiate into all three neural lineages, including dopaminergic neurons. J Neurochem 2008; 104:316–324.PubMedGoogle Scholar
  86. 86.
    Cho MS, Lee YE, Kim JY et al. Highly efficient and large-scale generation of functional dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA 2008; 105:3392–3397.CrossRefPubMedGoogle Scholar
  87. 87.
    Tomishima MJ, Hadjantonakis AK, Gong S et al. Production of green fluorescent protein transgenic embryonic stem cells using the GENSAT bacterial artificial chromosome library. Stem Cells 2007; 25:39–45.CrossRefPubMedGoogle Scholar
  88. 88.
    Zhao SL, Maxwell S, Jimenez-Beristain A et al. Generation of embryonic stem cells and transgenic mice expressing green fluorescence protein in midbrain dopaminergic neurons. Eur J Neurosci 2004; 19:1133–1140.CrossRefPubMedGoogle Scholar
  89. 89.
    Hedlund EM, Pruszak J, Lardaro T et al. Embryonic stem (ES) cell-derived Pitx3-eGFP midbrain dopamine neurons survive enrichment by FACS and function in an animal model of parkinson’s disease. Stem Cells 2008; 26:1526–1536.CrossRefPubMedGoogle Scholar
  90. 90.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126:663–676.CrossRefPubMedGoogle Scholar
  91. 91.
    Takahashi K, Tanabe K, Ohnuki M et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131:861–872.CrossRefPubMedGoogle Scholar
  92. 92.
    Wernig M, Meissner A, Foreman R et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 2007; 448:318–324.CrossRefPubMedGoogle Scholar
  93. 93.
    Maherali N, Sridharan R, Xie W et al. Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 2007; 1:55–70.CrossRefPubMedGoogle Scholar
  94. 94.
    Yu J, Vodyanik MA, Smuga-Otto K et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007; 318:1917–1920.CrossRefPubMedGoogle Scholar
  95. 95.
    Wernig M, Zhao JP, Pruszak J et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci USA 2008; 105:5856–5861.CrossRefPubMedGoogle Scholar

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© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  1. 1.Developmental Biology Program and Department of NeurosurgerySloan-Kettering Institute for Cancer ResearchNew York

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