Abstract
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.



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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 227:271–278
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 124:393–405
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 313:1172–1180
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 22:396–404
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 444:756–760
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 21:1200–1207
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 22:1246–1255
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 167:723–734
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 99:2344–2349
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 24:1433–1440
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 27:5849–5856
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 78:214–218
Brundin P, Hagell P (2001) The neurobiology of cell transplantation in Parkison’s disease. Clin Neurosci Res 1:507–520
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 495:473–496
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 9:179–195
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 123:1380–1390
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 21:657–668
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 171:98–108
Christophersen NS, Brundin P (2007) Large stem cell grafts could lead to erroneous interpretations of behavioral results? Nat Med 13:118–119
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 70:457–466
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 16:1829–1838
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 28:241–252
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 97:1467–1480
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 363:1432–1437
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 350:1353–1356
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 315:1243–1249
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 315:603–604
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 22:53–54
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 24:2170–2176
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 23:780–785
Eriksson PS, Perfilieva E, Bjork-Eriksson T, Alborn AM, Nordborg C, Peterson DA, Gage FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4:1313–1317
Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156
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 344:710–719
Freed CR, Breeze RE, Fahn S, Eidelberg D (2004) Preoperative response to levodopa is the best predictor of transplant outcome. Ann Neurol 55:896
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 24:115–124
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 24:763–771
Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438
Gage FH, Ray J, Fisher LJ (1995) Isolation, characterization, and use of stem cells from the CNS. Annu Rev Neurosci 18:159–192
Goldman SA, Roy NS, Beal MF, Cleren C (2007) Large stem cell grafts could lead to erroneous interpretations of behavioral results? Nat Med 13:118–119
Hagell P, Brundin P (2001) Cell survival and clinical outcome following intrastriatal transplantation in Parkinson disease. J Neuropathol Exp Neurol 60:741–752
Hagell P, Cenci MA (2005) Dyskinesias and dopamine cell replacement in Parkinson’s disease: a clinical perspective. Brain Res Bull 68:4–15
Hardy J, Cai H, Cookson MR, Gwinn-Hardy K, Singleton A (2006) Genetics of Parkinson’s disease and parkinsonism. Ann Neurol 60:389–398
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 56:179–187
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 73:236–248
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 24:351–357
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 129:233–244
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 75:817–824
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 1127:19–25
Jensen JB, Parmar M (2006) Strengths and limitations of the neurosphere culture system. Mol Neurobiol 34:153–161
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 364:172–178
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 22:149–156
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 28:31–40
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 99:1580–1585
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 106:621–625
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 24:557–567
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 203:394–405
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 418:50–56
Klimanskaya I, Chung Y, Meisner L, Johnson J, West MD, Lanza R (2005) Human embryonic stem cells derived without feeder cells. Lancet 365:1636–1641
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 6:213–219
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 22:334–345
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 18:675–679
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 316:67–70
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 24:10786–10795
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 277:38884–38894
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 1:55–70
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 37:1099–1103
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 38:1063–1075
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 21:165–180
Marshall JF, Ungerstedt U (1977) Striatal efferent fibers play a role in maintaining rotational behavior in the rat. Science 198:62–64
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 78:7634–7638
Martin MJ, Muotri A, Gage F, Varki A (2005) Human embryonic stem cells express an immunogenic nonhuman sialic acid. Nat Med 11:228–232
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 103:2874–2879
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 92:863–869
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 128:1498–1510
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 84:1682–1691
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 102:18644–18648
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 21:171–180
Okita K, Ichisaka T, Yamanaka S (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448:313–317
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 54:403–414
Olanow CW, Freeman TB, Kordower JH (2004) Preoperative response to levodopa is the best predictor of transplant outcome (author reply). Ann Neurol 55:896–897
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 15:3863–3875
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 22:798–811
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 164:215–226
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 134:43–55
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 66:983–995
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 23:471–476
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 92:1265–1276
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 20:2553–2555
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 359:99–103
Parmar M, Skogh C, Bjorklund A, Campbell K (2002) Regional specification of neurosphere cultures derived from subregions of the embryonic telencephalon. Mol Cell Neurosci 21:645–656
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 34:390–399
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 117:1269–1280
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 101:12543–12548
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 155:733–738
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 25:918–928
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 105:93–104
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 6:271–277
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 12:1259–1268
Samii A, Nutt JG, Ransom BR (2004) Parkinson’s disease. Lancet 363:1783–1793
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 427:740–744
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 22:1218–1238
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 12:302–308
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 26:12544–12555
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 19:1141–1152
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 25:411–418
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 148:135–146
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 115:102–109
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676
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 1045:80–87
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 25:6467–6477
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 282:1145–1147
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 103:9554–9559
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 98:779–784
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 printing
Wilson SI, Edlund T (2001) Neural induction: toward a unifying mechanism. Nat Neurosci 4 (Suppl):1161–1168
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 15:135–145
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 23:781–790
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 13:535–547
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 24:1695–1706
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 22:925–940
Zetterstrom RH, Solomin L, Jansson L, Hoffer BJ, Olson L, Perlmann T (1997) Dopamine neuron agenesis in Nurr1-deficient mice. Science 276:248–250
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 16:909–915
Acknowledgements
The authors’ own research on stem cells is supported by the following grants: The Swedish Research Council; Swedish Parkinson Foundation; Torsten och Ragnar Söderbergs stiftelser; Stiftelsen Olle Engkvist Byggmästare; Konung Gustaf V:s och Drottning Victorias Stiftelse; Swedish Brain Foundation; Swedish Institute.
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Morizane, A., Li, JY. & Brundin, P. From bench to bed: the potential of stem cells for the treatment of Parkinson’s disease. Cell Tissue Res 331, 323–336 (2008). https://doi.org/10.1007/s00441-007-0541-0
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DOI: https://doi.org/10.1007/s00441-007-0541-0
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