Cell and Tissue Research

, Volume 331, Issue 1, pp 323–336

From bench to bed: the potential of stem cells for the treatment of Parkinson’s disease



Parkinson’s disease (PD) is the most common movement disorder. The neuropathology is characterized by the loss of dopamine neurons in the substantia nigra pars compacta. Transplants of fetal/embryonic midbrain tissue have exhibited some beneficial clinical effects in open-label trials. Neural grafting has, however, not become a standard treatment for several reasons. First, the supply of donor cells is limited, and therefore, surgery is accompanied by difficult logistics. Second, the extent of beneficial effects has varied in a partly unpredictable manner. Third, some patients have exhibited graft-related side effects in the form of involuntary movements. Fourth, in two major double-blind placebo-controlled trials, there was no effect of the transplants on the primary endpoints. Nevertheless, neural transplantation continues to receive a great deal of interest, and now, attention is shifting to the idea of using stem cells as starting donor material. In the context of stem cell therapy for PD, stem cells can be divided into three categories: neural stem cells, embryonic stem cells, and other tissue-specific types of stem cells, e.g., bone marrow stem cells. Each type of stem cell is associated with advantages and disadvantages. In this article, we review recent advances of stem cell research of direct relevance to clinical application in PD and highlight the pros and cons of the different sources of cells. We draw special attention to some key problems that face the translation of stem cell technology into the clinical arena.


Stem cell Parkinson’s disease Transplantation Dopamine Neuron 


  1. Amit M, Carpenter MK, Inokuma MS, Chiu CP, Harris CP, Waknitz MA, Itskovitz-Eldor J, Thomson JA (2000) Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol 227:271–278PubMedGoogle Scholar
  2. Andersson E, Tryggvason U, Deng Q, Friling S, Alekseenko Z, Robert B, Perlmann T, Ericson J (2006) Identification of intrinsic determinants of midbrain dopamine neurons. Cell 124:393–405PubMedGoogle Scholar
  3. Andersson EK, Irvin DK, Ahlsio J, Parmar M (2007) Ngn2 and Nurr1 act in synergy to induce midbrain dopaminergic neurons from expanded neural stem and progenitor cells. Exp Cell Res 313:1172–1180PubMedGoogle Scholar
  4. Baier PC, Schindehutte J, Thinyane K, Flugge G, Fuchs E, Mansouri A, Paulus W, Gruss P, Trenkwalder C (2004) Behavioral changes in unilaterally 6-hydroxy-dopamine lesioned rats after transplantation of differentiated mouse embryonic stem cells without morphological integration. Stem Cells 22:396–404PubMedGoogle Scholar
  5. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD, Rich JN (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756–760PubMedGoogle Scholar
  6. Barberi T, Klivenyi P, Calingasan NY, Lee H, Kawamata H, Loonam K, Perrier AL, Bruses J, Rubio ME, Topf N, Tabar V, Harrison NL, Beal MF, Moore MA, Studer L (2003) Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat Biotechnol 21:1200–1207PubMedGoogle Scholar
  7. Ben-Hur T, Idelson M, Khaner H, Pera M, Reinhartz E, Itzik A, Reubinoff BE (2004) Transplantation of human embryonic stem cell-derived neural progenitors improves behavioral deficit in Parkinsonian rats. Stem Cells 22:1246–1255PubMedGoogle Scholar
  8. Bieberich E, Silva J, Wang G, Krishnamurthy K, Condie BG (2004) Selective apoptosis of pluripotent mouse and human stem cells by novel ceramide analogues prevents teratoma formation and enriches for neural precursors in ES cell-derived neural transplants. J Cell Biol 167:723–734PubMedGoogle Scholar
  9. Bjorklund LM, Sanchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 99:2344–2349PubMedGoogle Scholar
  10. Brederlau A, Correia AS, Anisimov SV, Elmi M, Roybon L, Paul G, Morizane A, Bergquist F, Riebe I, Nannmark U, Carta M, Hanse E, Takahashi J, Sasai Y, Funa K, Brundin P, Eriksson PS, Li JY (2006) 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 24:1433–1440PubMedGoogle Scholar
  11. Breysse N, Carlsson T, Winkler C, Bjorklund A, Kirik D (2007) The functional impact of the intrastriatal dopamine neuron grafts in parkinsonian rats is reduced with advancing disease. J Neurosci 27:5849–5856PubMedGoogle Scholar
  12. Brown VJ, Dunnett SB (1989) Comparison of adrenal and foetal nigral grafts on drug-induced rotation in rats with 6-OHDA lesions. Exp Brain Res 78:214–218PubMedGoogle Scholar
  13. Brundin P, Hagell P (2001) The neurobiology of cell transplantation in Parkison’s disease. Clin Neurosci Res 1:507–520Google Scholar
  14. Brundin P, Strecker RE, Lindvall O, Isacson O, Nilsson OG, Barbin G, Prochiantz A, Forni C, Nieoullon A, Widner H et al (1987) Intracerebral grafting of dopamine neurons. Experimental basis for clinical trials in patients with Parkinson’s disease. Ann N Y Acad Sci 495:473–496PubMedGoogle Scholar
  15. Brundin P, Karlsson J, Emgard M, Schierle GS, Hansson O, Petersen A, Castilho RF (2000a) Improving the survival of grafted dopaminergic neurons: a review over current approaches. Cell Transplant 9:179–195PubMedGoogle Scholar
  16. Brundin P, Pogarell O, Hagell P, Piccini P, Widner H, Schrag A, Kupsch A, Crabb L, Odin P, Gustavii B, Bjorklund A, Brooks DJ, Marsden CD, Oertel WH, Quinn NP, Rehncrona S, Lindvall O (2000b) Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson’s disease. Brain 123:1380–1390PubMedGoogle Scholar
  17. Carlsson T, Winkler C, Lundblad M, Cenci MA, Bjorklund A, Kirik D (2006) Graft placement and uneven pattern of reinnervation in the striatum is important for development of graft-induced dyskinesia. Neurobiol Dis 21:657–668PubMedGoogle Scholar
  18. Carvey PM, Ling ZD, Sortwell CE, Pitzer MR, McGuire SO, Storch A, Collier TJ (2001) A clonal line of mesencephalic progenitor cells converted to dopamine neurons by hematopoietic cytokines: a source of cells for transplantation in Parkinson’s disease. Exp Neurol 171:98–108PubMedGoogle Scholar
  19. Christophersen NS, Brundin P (2007) Large stem cell grafts could lead to erroneous interpretations of behavioral results? Nat Med 13:118–119PubMedGoogle Scholar
  20. Christophersen NS, Meijer X, Jorgensen JR, Englund U, Gronborg M, Seiger A, Brundin P, Wahlberg LU (2006) Induction of dopaminergic neurons from growth factor expanded neural stem/progenitor cell cultures derived from human first trimester forebrain. Brain Res Bull 70:457–466PubMedGoogle Scholar
  21. Chung S, Sonntag KC, Andersson T, Bjorklund LM, Park JJ, Kim DW, Kang UJ, Isacson O, Kim KS (2002) Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neurons. Eur J Neurosci 16:1829–1838PubMedGoogle Scholar
  22. Chung S, Hedlund E, Hwang M, Kim DW, Shin BS, Hwang DY, Jung Kang U, Isacson O, Kim KS (2005) The homeodomain transcription factor Pitx3 facilitates differentiation of mouse embryonic stem cells into AHD2-expressing dopaminergic neurons. Mol Cell Neurosci 28:241–252PubMedGoogle Scholar
  23. Chung S, Shin BS, Hedlund E, Pruszak J, Ferree A, Kang UJ, Isacson O, Kim KS (2006) Genetic selection of sox1GFP-expressing neural precursors removes residual tumorigenic pluripotent stem cells and attenuates tumor formation after transplantation. J Neurochem 97:1467–1480PubMedGoogle Scholar
  24. Cogle CR, Yachnis AT, Laywell ED, Zander DS, Wingard JR, Steindler DA, Scott EW (2004) Bone marrow transdifferentiation in brain after transplantation: a retrospective study. Lancet 363:1432–1437PubMedGoogle Scholar
  25. Cowan CA, Klimanskaya I, McMahon J, Atienza J, Witmyer J, Zucker JP, Wang S, Morton CC, McMahon AP, Powers D, Melton DA (2004) Derivation of embryonic stem-cell lines from human blastocysts. N Engl J Med 350:1353–1356PubMedGoogle Scholar
  26. Curtis MA, Kam M, Nannmark U, Anderson MF, Axell MZ, Wikkelso C, Holtas S, Roon-Mom WM van, Bjork-Eriksson T, Nordborg C, Frisen J, Dragunow M, Faull RL, Eriksson PS (2007) Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science 315:1243–1249PubMedGoogle Scholar
  27. Daley GQ, Richter LA, Auerbach JM, Benvenisty N, Charo RA, Chen G, Deng HK, Goldstein LS, Hudson KL, Hyun I, Junn SC, Love J, Lee EH, McLaren A, Mummery CL, Nakatsuji N, Racowsky C, Rooke H, Rossant J, Scholer HR, Solbakk JH, Taylor P, Trounson AO, Weissman IL, Wilmut I, Yu J, Zoloth L (2007) Ethics. The ISSCR guidelines for human embryonic stem cell research. Science 315:603–604PubMedGoogle Scholar
  28. Draper JS, Smith K, Gokhale P, Moore HD, Maltby E, Johnson J, Meisner L, Zwaka TP, Thomson JA, Andrews PW (2004) Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells. Nat Biotechnol 22:53–54PubMedGoogle Scholar
  29. Ellerstrom C, Strehl R, Moya K, Andersson K, Bergh C, Lundin K, Hyllner J, Semb H (2006) Derivation of a xeno-free human embryonic stem cell line. Stem Cells 24:2170–2176PubMedGoogle Scholar
  30. Erdo F, Buhrle C, Blunk J, Hoehn M, Xia Y, Fleischmann B, Focking M, Kustermann E, Kolossov E, Hescheler J, Hossmann KA, Trapp T (2003) Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab 23:780–785PubMedGoogle Scholar
  31. Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317PubMedGoogle Scholar
  32. Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156PubMedGoogle Scholar
  33. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S (2001) Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 344:710–719PubMedGoogle Scholar
  34. Freed CR, Breeze RE, Fahn S, Eidelberg D (2004) Preoperative response to levodopa is the best predictor of transplant outcome. Ann Neurol 55:896PubMedGoogle Scholar
  35. Fu YS, Cheng YC, Lin MY, Cheng H, Chu PM, Chou SC, Shih YH, Ko MH, Sung MS (2006) Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells 24:115–124PubMedGoogle Scholar
  36. Fukuda H, Takahashi J, Watanabe K, Hayashi H, Morizane A, Koyanagi M, Sasai Y, Hashimoto N (2006) Fluorescence-activated cell sorting-based purification of embryonic stem cell-derived neural precursors averts tumor formation after transplantation. Stem Cells 24:763–771PubMedGoogle Scholar
  37. Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438PubMedGoogle Scholar
  38. Gage FH, Ray J, Fisher LJ (1995) Isolation, characterization, and use of stem cells from the CNS. Annu Rev Neurosci 18:159–192PubMedGoogle Scholar
  39. Goldman SA, Roy NS, Beal MF, Cleren C (2007) Large stem cell grafts could lead to erroneous interpretations of behavioral results? Nat Med 13:118–119PubMedGoogle Scholar
  40. Hagell P, Brundin P (2001) Cell survival and clinical outcome following intrastriatal transplantation in Parkinson disease. J Neuropathol Exp Neurol 60:741–752PubMedGoogle Scholar
  41. Hagell P, Cenci MA (2005) Dyskinesias and dopamine cell replacement in Parkinson’s disease: a clinical perspective. Brain Res Bull 68:4–15PubMedGoogle Scholar
  42. Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Singleton A (2006) Genetics of Parkinson’s disease and parkinsonism. Ann Neurol 60:389–398PubMedGoogle Scholar
  43. Hauser RA, Freeman TB, Snow BJ, Nauert M, Gauger L, Kordower JH, Olanow CW (1999) Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease. Arch Neurol 56:179–187PubMedGoogle Scholar
  44. Herman JP, Lupp A, Abrous N, Le Moal M, Hertting G, Jackisch R (1988) Intrastriatal dopaminergic grafts restore inhibitory control over striatal cholinergic neurons. Exp Brain Res 73:236–248PubMedGoogle Scholar
  45. Herszfeld D, Wolvetang E, Langton-Bunker E, Chung TL, Filipczyk AA, Houssami S, Jamshidi P, Koh K, Laslett AL, Michalska A, Nguyen L, Reubinoff BE, Tellis I, Auerbach JM, Ording CJ, Looijenga LH, Pera MF (2006) CD30 is a survival factor and a biomarker for transformed human pluripotent stem cells. Nat Biotechnol 24:351–357PubMedGoogle Scholar
  46. Hitoshi S, Tropepe V, Ekker M, Kooy D van der (2002) Neural stem cell lineages are regionally specified, but not committed, within distinct compartments of the developing brain. Development 129:233–244PubMedGoogle Scholar
  47. Horiguchi S, Takahashi J, Kishi Y, Morizane A, Okamoto Y, Koyanagi M, Tsuji M, Tashiro K, Honjo T, Fujii S, Hashimoto N (2004) Neural precursor cells derived from human embryonic brain retain regional specificity. J Neurosci Res 75:817–824PubMedGoogle Scholar
  48. Iacovitti L, Donaldson AE, Marshall CE, Suon S, Yang M (2007) A protocol for the differentiation of human embryonic stem cells into dopaminergic neurons using only chemically defined human additives: studies in vitro and in vivo. Brain Res 1127:19–25PubMedGoogle Scholar
  49. Jensen JB, Parmar M (2006) Strengths and limitations of the neurosphere culture system. Mol Neurobiol 34:153–161PubMedGoogle Scholar
  50. Joannides A, Gaughwin P, Schwiening C, Majed H, Sterling J, Compston A, Chandran S (2004) Efficient generation of neural precursors from adult human skin: astrocytes promote neurogenesis from skin-derived stem cells. Lancet 364:172–178PubMedGoogle Scholar
  51. Kanda S, Tamada Y, Yoshidome A, Hayashi I, Nishiyama T (2004) Over-expression of bHLH genes facilitate neural formation of mouse embryonic stem (ES) cells in vitro. Int J Dev Neurosci 22:149–156PubMedGoogle Scholar
  52. Kawasaki H, Mizuseki K, Nishikawa S, Kaneko S, Kuwana Y, Nakanishi S, Nishikawa SI, Sasai Y (2000) Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 28:31–40PubMedGoogle Scholar
  53. Kawasaki H, Suemori H, Mizuseki K, Watanabe K, Urano F, Ichinose H, Haruta M, Takahashi M, Yoshikawa K, Nishikawa S, Nakatsuji N, Sasai Y (2002) Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity. Proc Natl Acad Sci USA 99:1580–1585PubMedGoogle Scholar
  54. Kenney C, Simpson R, Hunter C, Ondo W, Almaguer M, Davidson A, Jankovic J (2007) Short-term and long-term safety of deep brain stimulation in the treatment of movement disorders. J Neurosurg 106:621–625PubMedGoogle Scholar
  55. Kim DW, Chung S, Hwang M, Ferree A, Tsai HC, Park JJ, Chung S, Nam TS, Kang UJ, Isacson O, Kim KS (2006) Stromal cell-derived inducing activity, Nurr1, and signaling molecules synergistically induce dopaminergic neurons from mouse embryonic stem cells. Stem Cells 24:557–567PubMedGoogle Scholar
  56. Kim HJ, Sugimori M, Nakafuku M, Svendsen CN (2007) Control of neurogenesis and tyrosine hydroxylase expression in neural progenitor cells through bHLH proteins and Nurr1. Exp Neurol 203:394–405PubMedGoogle Scholar
  57. Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N, Lee SH, Nguyen J, Sanchez-Pernaute R, Bankiewicz K, McKay R (2002) Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 418:50–56PubMedGoogle Scholar
  58. Klimanskaya I, Chung Y, Meisner L, Johnson J, West MD, Lanza R (2005) Human embryonic stem cells derived without feeder cells. Lancet 365:1636–1641PubMedGoogle Scholar
  59. Kordower JH, Styren S, Clarke M, DeKosky ST, Olanow CW, Freeman TB (1997) Fetal grafting for Parkinson’s disease: expression of immune markers in two patients with functional fetal nigral implants. Cell Transplant 6:213–219PubMedGoogle Scholar
  60. Lane EL, Winkler C, Brundin P, Cenci MA (2006) The impact of graft size on the development of dyskinesia following intrastriatal grafting of embryonic dopamine neurons in the rat. Neurobiol Dis 22:334–345PubMedGoogle Scholar
  61. Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD (2000) Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 18:675–679PubMedGoogle Scholar
  62. Li Y, Chen J, Wang L, Zhang L, Lu M, Chopp M (2001) Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neurosci Lett 316:67–70PubMedGoogle Scholar
  63. Liste I, Garcia-Garcia E, Martinez-Serrano A (2004) The generation of dopaminergic neurons by human neural stem cells is enhanced by Bcl-XL, both in vitro and in vivo. J Neurosci 24:10786–10795PubMedGoogle Scholar
  64. Lotharius J, Barg S, Wiekop P, Lundberg C, Raymon HK, Brundin P (2002) Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line. J Biol Chem 277:38884–38894PubMedGoogle Scholar
  65. Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K (2007) Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. Cell Stem Cell 1:55–70PubMedGoogle Scholar
  66. Maitra A, Arking DE, Shivapurkar N, Ikeda M, Stastny V, Kassauei K, Sui G, Cutler DJ, Liu Y, Brimble SN, Noaksson K, Hyllner J, Schulz TC, Zeng X, Freed WJ, Crook J, Abraham S, Colman A, Sartipy P, Matsui S, Carpenter M, Gazdar AF, Rao M, Chakravarti A (2005) Genomic alterations in cultured human embryonic stem cells. Nat Genet 37:1099–1103PubMedGoogle Scholar
  67. Mallon BS, Park KY, Chen KG, Hamilton RS, McKay RD (2006) Toward xeno-free culture of human embryonic stem cells. Int J Biochem Cell Biol 38:1063–1075PubMedGoogle Scholar
  68. Maries E, Kordower JH, Chu Y, Collier TJ, Sortwell CE, Olaru E, Shannon K, Steece-Collier K (2006) Focal not widespread grafts induce novel dyskinetic behavior in parkinsonian rats. Neurobiol Dis 21:165–180PubMedGoogle Scholar
  69. Marshall JF, Ungerstedt U (1977) Striatal efferent fibers play a role in maintaining rotational behavior in the rat. Science 198:62–64PubMedGoogle Scholar
  70. Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78:7634–7638PubMedGoogle Scholar
  71. Martin MJ, Muotri A, Gage F, Varki A (2005) Human embryonic stem cells express an immunogenic nonhuman sialic acid. Nat Med 11:228–232PubMedGoogle Scholar
  72. Martinat C, Bacci JJ, Leete T, Kim J, Vanti WB, Newman AH, Cha JH, Gether U, Wang H, Abeliovich A (2006) Cooperative transcription activation by Nurr1 and Pitx3 induces embryonic stem cell maturation to the midbrain dopamine neuron phenotype. Proc Natl Acad Sci USA 103:2874–2879PubMedGoogle Scholar
  73. Mendez I, Dagher A, Hong M, Hebb A, Gaudet P, Law A, Weerasinghe S, King D, Desrosiers J, Darvesh S, Acorn T, Robertson H (2000) Enhancement of survival of stored dopaminergic cells and promotion of graft survival by exposure of human fetal nigral tissue to glial cell line-derived neurotrophic factor in patients with Parkinson’s disease. Report of two cases and technical considerations. J Neurosurg 92:863–869PubMedGoogle Scholar
  74. Mendez I, Sanchez-Pernaute R, Cooper O, Vinuela A, Ferrari D, Bjorklund L, Dagher A, Isacson O (2005) Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease. Brain 128:1498–1510PubMedGoogle Scholar
  75. Mori H, Ninomiya K, Kino-oka M, Shofuda T, Islam MO, Yamasaki M, Okano H, Taya M, Kanemura Y (2006) Effect of neurosphere size on the growth rate of human neural stem/progenitor cells. J Neurosci Res 84:1682–1691PubMedGoogle Scholar
  76. Muotri AR, Nakashima K, Toni N, Sandler VM, Gage FH (2005) Development of functional human embryonic stem cell-derived neurons in mouse brain. Proc Natl Acad Sci USA 102:18644–18648PubMedGoogle Scholar
  77. Nishimura F, Yoshikawa M, Kanda S, Nonaka M, Yokota H, Shiroi A, Nakase H, Hirabayashi H, Ouji Y, Birumachi J, Ishizaka S, Sakaki T (2003) Potential use of embryonic stem cells for the treatment of mouse parkinsonian models: improved behavior by transplantation of in vitro differentiated dopaminergic neurons from embryonic stem cells. Stem Cells 21:171–180PubMedGoogle Scholar
  78. Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317PubMedGoogle Scholar
  79. Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB (2003) A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 54:403–414PubMedGoogle Scholar
  80. Olanow CW, Freeman TB, Kordower JH (2004) Preoperative response to levodopa is the best predictor of transplant outcome (author reply). Ann Neurol 55:896–897Google Scholar
  81. Olsson M, Nikkhah G, Bentlage C, Bjorklund A (1995) Forelimb akinesia in the rat Parkinson model: differential effects of dopamine agonists and nigral transplants as assessed by a new stepping test. J Neurosci 15:3863–3875PubMedGoogle Scholar
  82. Ostenfeld T, Svendsen CN (2004) Requirement for neurogenesis to proceed through the division of neuronal progenitors following differentiation of epidermal growth factor and fibroblast growth factor-2-responsive human neural stem cells. Stem Cells 22:798–811PubMedGoogle Scholar
  83. Ostenfeld T, Caldwell MA, Prowse KR, Linskens MH, Jauniaux E, Svendsen CN (2000) Human neural precursor cells express low levels of telomerase in vitro and show diminishing cell proliferation with extensive axonal outgrowth following transplantation. Exp Neurol 164:215–226PubMedGoogle Scholar
  84. Ostenfeld T, Joly E, Tai YT, Peters A, Caldwell M, Jauniaux E, Svendsen CN (2002) Regional specification of rodent and human neurospheres. Brain Res Dev Brain Res 134:43–55PubMedGoogle Scholar
  85. Pahwa R, Factor SA, Lyons KE, Ondo WG, Gronseth G, Bronte-Stewart H, Hallett M, Miyasaki J, Stevens J, Weiner WJ (2006) Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 66:983–995PubMedGoogle Scholar
  86. Parish CL, Parisi S, Persico MG, Arenas E, Minchiotti G (2005) Cripto as a target for improving embryonic stem cell-based therapy in Parkinson’s disease. Stem Cells 23:471–476PubMedGoogle Scholar
  87. Park CH, Minn YK, Lee JY, Choi DH, Chang MY, Shim JW, Ko JY, Koh HC, Kang MJ, Kang JS, Rhie DJ, Lee YS, Son H, Moon SY, Kim KS, Lee SH (2005) In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J Neurochem 92:1265–1276PubMedGoogle Scholar
  88. Park CH, Kang JS, Shin YH, Chang MY, Chung S, Koh HC, Zhu MH, Oh SB, Lee YS, Panagiotakos G, Tabar V, Studer L, Lee SH (2006) Acquisition of in vitro and in vivo functionality of Nurr1-induced dopamine neurons. FASEB J 20:2553–2555PubMedGoogle Scholar
  89. Park S, Lee KS, Lee YJ, Shin HA, Cho HY, Wang KC, Kim YS, Lee HT, Chung KS, Kim EY, Lim J (2004) Generation of dopaminergic neurons in vitro from human embryonic stem cells treated with neurotrophic factors. Neurosci Lett 359:99–103PubMedGoogle Scholar
  90. Parmar M, Skogh C, Bjorklund A, Campbell K (2002) Regional specification of neurosphere cultures derived from subregions of the embryonic telencephalon. Mol Cell Neurosci 21:645–656PubMedGoogle Scholar
  91. Paul G, Christophersen NS, Raymon H, Kiaer C, Smith R, Brundin P (2007) Tyrosine hydroxylase expression is unstable in a human immortalized mesencephalic cell line—studies in vitro and after intracerebral grafting in vivo. Mol Cell Neurosci 34:390–399PubMedGoogle Scholar
  92. Pera MF, Andrade J, Houssami S, Reubinoff B, Trounson A, Stanley EG, Ward-van Oostwaard D, Mummery C (2004) Regulation of human embryonic stem cell differentiation by BMP-2 and its antagonist Noggin. J Cell Sci 117:1269–1280PubMedGoogle Scholar
  93. Perrier AL, Tabar V, Barberi T, Rubio ME, Bruses J, Topf N, Harrison NL, Studer L (2004) Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA 101:12543–12548PubMedGoogle Scholar
  94. Priller J, Persons DA, Klett FF, Kempermann G, Kreutzberg GW, Dirnagl U (2001) Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J Cell Biol 155:733–738PubMedGoogle Scholar
  95. Rodriguez-Gomez JA, Lu JQ, Velasco I, Rivera S, Zoghbi SS, Liow JS, Musachio JL, Chin FT, Toyama H, Seidel J, Green MV, Thanos PK, Ichise M, Pike VW, Innis RB, McKay RD (2007) Persistent dopamine functions of neurons derived from embryonic stem cells in a rodent model of Parkinson’s disease. Stem Cells 25:918–928PubMedGoogle Scholar
  96. Rolletschek A, Chang H, Guan K, Czyz J, Meyer M, Wobus AM (2001) Differentiation of embryonic stem cell-derived dopaminergic neurons is enhanced by survival-promoting factors. Mech Dev 105:93–104PubMedGoogle Scholar
  97. Roy NS, Wang S, Jiang L, Kang J, Benraiss A, Harrison-Restelli C, Fraser RA, Couldwell WT, Kawaguchi A, Okano H, Nedergaard M, Goldman SA (2000) In vitro neurogenesis by progenitor cells isolated from the adult human hippocampus. Nat Med 6:271–277PubMedGoogle Scholar
  98. Roy NS, Cleren C, Singh SK, Yang L, Beal MF, Goldman SA (2006) Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med 12:1259–1268PubMedGoogle Scholar
  99. Samii A, Nutt JG, Ransom BR (2004) Parkinson’s disease. Lancet 363:1783–1793PubMedGoogle Scholar
  100. Sanai N, Tramontin AD, Quinones-Hinojosa A, Barbaro NM, Gupta N, Kunwar S, Lawton MT, McDermott MW, Parsa AT, Manuel-Garcia Verdugo J, Berger MS, Alvarez-Buylla A (2004) Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 427:740–744PubMedGoogle Scholar
  101. Schulz TC, Noggle SA, Palmarini GM, Weiler DA, Lyons IG, Pensa KA, Meedeniya AC, Davidson BP, Lambert NA, Condie BG (2004) Differentiation of human embryonic stem cells to dopaminergic neurons in serum-free suspension culture. Stem Cells 22:1218–1238PubMedGoogle Scholar
  102. Schwarz SC, Wittlinger J, Schober R, Storch A, Schwarz J (2006) Transplantation of human neural precursor cells in the 6-OHDA lesioned rats: effect of immunosuppression with cyclosporine A. Parkinsonism Relat Disord 12:302–308PubMedGoogle Scholar
  103. Sim FJ, Keyoung HM, Goldman JE, Kim DK, Jung HW, Roy NS, Goldman SA (2006) Neurocytoma is a tumor of adult neuronal progenitor cells. J Neurosci 26:12544–12555PubMedGoogle Scholar
  104. Sonntag KC, Simantov R, Kim KS, Isacson O (2004) Temporally induced Nurr1 can induce a non-neuronal dopaminergic cell type in embryonic stem cell differentiation. Eur J Neurosci 19:1141–1152PubMedGoogle Scholar
  105. Sonntag KC, Pruszak J, Yoshizaki T, Arensbergen J van, Sanchez-Pernaute R, Isacson O (2007) Enhanced yield of neuroepithelial precursors and midbrain-like dopaminergic neurons from human embryonic stem cells using the BMP antagonist Noggin. Stem Cells 25:411–418PubMedGoogle Scholar
  106. Svendsen CN, Caldwell MA, Shen J, Borg MG ter, Rosser AE, Tyers P, Karmiol S, Dunnett SB (1997) Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson’s disease. Exp Neurol 148:135–146PubMedGoogle Scholar
  107. Takagi Y, Takahashi J, Saiki H, Morizane A, Hayashi T, Kishi Y, Fukuda H, Okamoto Y, Koyanagi M, Ideguchi M, Hayashi H, Imazato T, Kawasaki H, Suemori H, Omachi S, Iida H, Itoh N, Nakatsuji N, Sasai Y, Hashimoto N (2005) Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J Clin Invest 115:102–109PubMedGoogle Scholar
  108. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedGoogle Scholar
  109. Thinyane K, Baier PC, Schindehutte J, Mansouri A, Paulus W, Trenkwalder C, Flugge G, Fuchs E (2005) Fate of pre-differentiated mouse embryonic stem cells transplanted in unilaterally 6-hydroxydopamine lesioned rats: histological characterization of the grafted cells. Brain Res 1045:80–87PubMedGoogle Scholar
  110. Thompson L, Barraud P, Andersson E, Kirik D, Bjorklund A (2005) Identification of dopaminergic neurons of nigral and ventral tegmental area subtypes in grafts of fetal ventral mesencephalon based on cell morphology, protein expression, and efferent projections. J Neurosci 25:6467–6477PubMedGoogle Scholar
  111. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147PubMedGoogle Scholar
  112. Ueno M, Matsumura M, Watanabe K, Nakamura T, Osakada F, Takahashi M, Kawasaki H, Kinoshita S, Sasai Y (2006) Neural conversion of ES cells by an inductive activity on human amniotic membrane matrix. Proc Natl Acad Sci USA 103:9554–9559PubMedGoogle Scholar
  113. Umemura A, Jaggi JL, Hurtig HI, Siderowf AD, Colcher A, Stern MB, Baltuch GH (2003) Deep brain stimulation for movement disorders: morbidity and mortality in 109 patients. J Neurosurg 98:779–784PubMedCrossRefGoogle Scholar
  114. Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (2007) In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature: e-published ahead of printingGoogle Scholar
  115. Wilson SI, Edlund T (2001) Neural induction: toward a unifying mechanism. Nat Neurosci 4 (Suppl):1161–1168PubMedGoogle Scholar
  116. Yamazoe H, Kobori M, Murakami Y, Yano K, Satoh M, Mizuseki K, Sasai Y, Iwata H (2006) One-step induction of neurons from mouse embryonic stem cells in serum-free media containing vitamin B12 and heparin. Cell Transplant 15:135–145PubMedGoogle Scholar
  117. Yan Y, Yang D, Zarnowska ED, Du Z, Werbel B, Valliere C, Pearce RA, Thomson JA, Zhang SC (2005) Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells 23:781–790PubMedGoogle Scholar
  118. Yang M, Donaldson AE, Marshall CE, Shen J, Iacovitti L (2004) Studies on the differentiation of dopaminergic traits in human neural progenitor cells in vitro and in vivo. Cell Transplant 13:535–547PubMedGoogle Scholar
  119. Yue F, Cui L, Johkura K, Ogiwara N, Sasaki K (2006) Induction of midbrain dopaminergic neurons from primate embryonic stem cells by coculture with Sertoli cells. Stem Cells 24:1695–1706PubMedGoogle Scholar
  120. Zeng X, Cai J, Chen J, Luo Y, You ZB, Fotter E, Wang Y, Harvey B, Miura T, Backman C, Chen GJ, Rao MS, Freed WJ (2004) Dopaminergic differentiation of human embryonic stem cells. Stem Cells 22:925–940PubMedGoogle Scholar
  121. Zetterstrom RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250PubMedGoogle Scholar
  122. Zhang QB, Ji XY, Huang Q, Dong J, Zhu YD, Lan Q (2006) Differentiation profile of brain tumor stem cells: a comparative study with neural stem cells. Cell Res 16:909–915PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical ScienceLund UniversityLundSweden

Personalised recommendations