, Volume 1, Issue 4, pp 382–393 | Cite as

Cell therapy in Parkinson’s disease

  • Olle LindvallEmail author
  • Anders BjörklundEmail author


The clinical studies with intrastriatal transplants of fetal mesencephalic tissue in Parkinson’s disease (PD) patients have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine (DA) release and movement-related frontal cortical activation, and give rise to significant symptomatic relief. In the most successful cases, patients have been able to withdrawl-dopa treatment after transplantation and resume an independent life. However, there are currently several problems linked to the use of fetal tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients, 2) variability of functional outcome with some patients showing major improvement and others modest if any clinical benefit, and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in PD. For the development of a clinically useful cell therapy, we need to define better criteria for patient selection and how graft placement should be optimized in each patient. We also need to explore in more detail the importance for functional outcome of the dissection and cellular composition of the graft tissue as well as of immunological mechanisms. Strategies to prevent the development of dyskinesias after grafting have to be developed. Finally, we need to generate large numbers of viable DA neurons in preparations that are standardized and quality controlled. The stem cell technology may provide a virtually unlimited source of DA neurons, but several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.

Key Words

Parkinson’s disease transplantation stem cells neural grafts dopamine 


  1. 1.
    Lindvall O, Brundin P, Widner H, Rehncrona S, Gustavii B, Frackowiak R et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease.Science 247: 574–577, 1990.PubMedCrossRefGoogle Scholar
  2. 2.
    Lindvall O, Widner H, Rehncrona S, Brundin P, Odin P, Gustavii B et al. Transplantation of fetal dopamine neurons in Parkinson’s disease: one-year clinical and neurophysiological observations in two patients with putaminal implants.Ann Neurol 31: 155–165, 1992.PubMedCrossRefGoogle Scholar
  3. 3.
    Lindvall O, Sawle G, Widner H, Rothwell JC, Bjorklund A, Brooks D et al. Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease.Ann Neurol 35: 172–180, 1994.PubMedCrossRefGoogle Scholar
  4. 4.
    Sawle GV, Bloomfield PM, Bjorklund A, Brooks DJ, Brundin P, Leenders, KL et al. Transplantation of fetal dopamine neurons in Parkinson’s disease: PET [18F]6-l-fluorodopa studies in two patients with putaminal implants.Ann Neurol 31: 166–173, 1992.PubMedCrossRefGoogle Scholar
  5. 5.
    Widner H, Tetrud J, Rehncrona S, Snow B, Brundin P, Gustavii B et al. Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).N Engl J Med 327: 1556–1563, 1992.PubMedCrossRefGoogle Scholar
  6. 6.
    Peschanski M, Defer G, N’Guyen JP, Ricolfi F, Monfort JC, Remy P et al. Bilateral motor improvement and alteration ofl-dopa effect in two patients with Parkinson’s disease following intrastriatal transplantation of foetal ventral mesencephalon.Brain 117: 487–499, 1994.PubMedCrossRefGoogle Scholar
  7. 7.
    Freeman TB, Olanow CW, Hauser RA, Nauert GM, Smith DA, Borlongan CV et al. Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson’s disease.Ann Neurol 38: 379–388, 1995.PubMedCrossRefGoogle Scholar
  8. 8.
    Remy P, Samson Y, Hantraye P, Fontaine A, Defer G, Mangin JF et al. Clinical correlates of [18F]fluorodopa uptake in five grafted parkinsonian patients.Ann Neurol 38: 580–588, 1995.PubMedCrossRefGoogle Scholar
  9. 9.
    Defer GL, Geny C, Ricolfi F, Fenelon G, Monfort JC, Remy P et al. Long-term outcome of unilaterally transplanted parkinsonian patients. I. Clinical approach.Brain 119: 41–50, 1996.PubMedCrossRefGoogle Scholar
  10. 10.
    Wenning GK, Odin P, Morrish P, Rehncrona S, Widner H, Brundin P et al. Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson’s disease.Ann Neurol 42: 95–107, 1997.PubMedCrossRefGoogle Scholar
  11. 11.
    Hagell P, Schrag A, Piccini P, Jahanshahi M, Brown R, Rehncrona S et al. Sequential bilateral transplantation in Parkinson’s disease: effects of the second graft.Brain 122: 1121–1132, 1999.PubMedCrossRefGoogle Scholar
  12. 12.
    Hauser RA, Freeman TB, Snow BJ, Nauert M, Gauger L, Kordower JH et al. Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease.Arch Neurol 56: 179–187, 1999.PubMedCrossRefGoogle Scholar
  13. 13.
    Brundin P, Pogarell O, Hagell P, Piccini P, Widner H, Schrag A et al. Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson’s disease.Brain 123: 1380–1390, 2000.PubMedCrossRefGoogle Scholar
  14. 14.
    Mendez I, Dagher A, Hong M, Hebb A, Gaudet P, Law A et al. 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, 2000.PubMedCrossRefGoogle Scholar
  15. 15.
    Mendez I, Dagher A, Hong M, Gaudet P, Weerasinghe S, McAlister V et al. Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study. Report of three cases.J Neurosurg 96: 589–596, 2002.PubMedCrossRefGoogle Scholar
  16. 16.
    Cochen V, Ribeiro MJ, Nguyen JP, Gurruchaga JM, Villafane G, Loc’h C et al. Transplantation in Parkinson’s disease: PET changes correlate with the amount of grafted tissue.Mov Disord 18: 928–932, 2003.PubMedCrossRefGoogle Scholar
  17. 17.
    Piccini P, Brooks DJ, Bjorklund A, Gunn RN, Grasby PM, Rimoldi O et al. Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient.Nat Neurosci 2: 1137–1140, 1999.PubMedCrossRefGoogle Scholar
  18. 18.
    Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease.N Engl J Med 344: 710–719, 2001.PubMedCrossRefGoogle Scholar
  19. 19.
    Kordower JH, Freeman TB, Chen EY, Mufson EJ, Sanberg PR, Hauser RA et al. Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson’s disease.Mov Disord 13: 383–393, 1998.PubMedCrossRefGoogle Scholar
  20. 20.
    Kordower JH, Freeman TB, Snow BJ, Vingerhoets FJ, Mufson EJ, Sanberg PR et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease.N Engl J Med 332: 1118–1124, 1995.PubMedCrossRefGoogle Scholar
  21. 21.
    Kordower JH, Rosenstein JM, Collier TJ, Burke MA, Chen EY, Li JM et al. Functional fetal nigral grafts in a patient with Parkinson’s disease: chemoanatomic, ultrastructural, and metabolic studies.J Comp Neurol 370: 203–230, 1996.PubMedCrossRefGoogle Scholar
  22. 22.
    Hagell P, Brundin P. Cell survival and clinical outcome following intrastriatal transplantation in Parkinson disease.J Neuropathol Exp Neurol 60: 741–752, 2001.PubMedGoogle Scholar
  23. 23.
    Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease.Ann Neurol 54: 403–414, 2003.PubMedCrossRefGoogle Scholar
  24. 24.
    Playford ED, Jenkins IH, Passingham RE, Nutt J, Frackowiak RS, Brooks DJ. Impaired mesial frontal and putamen activation in Parkinson’s disease: a positron emission tomography study.Ann Neurol 32: 151–161, 1992.PubMedCrossRefGoogle Scholar
  25. 25.
    Piccini P, Lindvall O, Bjorklund A, Brundin P, Hagell P, Ceravolo R et al. Delayed recovery of movement-related cortical function in Parkinson’s disease after striatal dopaminergic grafts.Ann Neurol 48: 689–695, 2000.PubMedCrossRefGoogle Scholar
  26. 26.
    Cenci MA, Hagell P. Dyskinesias and neural grafting in Parkinson’s disease. In: Restorative therapies in Parkinson’s disease (Olanow CW, Brundin P, eds). New York: Kluwer Academic/Plenum Publishers (in press).Google Scholar
  27. 27.
    Hagell P, Piccini P, Bjorklund A, Brundin P, Rehncrona S, Widner H et al. Dyskinesias following neural transplantation in Parkinson’s disease.Nat Neurosci 5: 627–628, 2002.PubMedGoogle Scholar
  28. 28.
    Ma Y, Feigin A, Dhawan V, Fukuda M, Shi Q, Greene P et al. Dyskinesia after fetal cell transplantation for parkinsonism: a PET study.Ann Neurol 52: 628–634, 2002.PubMedCrossRefGoogle Scholar
  29. 29.
    Lindvall O, Hagell P. Clinical observations after neural transplantation in Parkinson’s disease.Prog Brain Res 127: 299–320, 2000.PubMedCrossRefGoogle Scholar
  30. 30.
    Vitek JL. Deep brain stimulation for Parkinson’s disease. A critical re-evaluation of STN versus GPi DBS.Stereotact Funct Neurosurg 78: 119–131, 2002.PubMedCrossRefGoogle Scholar
  31. 31.
    Braak H, Braak E. Pathoanatomy of Parkinson’s disease.J Neurol 247 [Suppl 2]: II3-II10, 2000.PubMedCrossRefGoogle Scholar
  32. 32.
    Perl DP, Olanow CW, Calne D. Alzheimer’s disease and Parkinson’s disease: distinct entities or extremes of a spectrum of neurodegeneration?Ann Neurol 44: S19-S31, 1998.PubMedGoogle Scholar
  33. 33.
    Agid Y, Javoy-Agid F, Ruberg M. Biochemistry of neurotransmitter in PD. In: Movement disorders 2 (Marsden CD, Fahn S, eds), pp 166–230. London: Butterworth, 1987.Google Scholar
  34. 34.
    Sortwell CE, Camargo MD, Pitzer MR, Gyawali S, Collier TJ. Diminished survival of mesencephalic dopamine neurons grafted into aged hosts occurs during the immediate postgrafting interval.Exp Neurol 169: 23–29, 2001.PubMedCrossRefGoogle Scholar
  35. 35.
    Doucet G, Brundin P, Descarries L, Bjorklund A. Effect of prior dopamine denervation on survival and fiber outgrowth from intrastriatal fetal mesencephalic grafts.Eur J Neurosci 2: 279–290, 1990.PubMedCrossRefGoogle Scholar
  36. 36.
    Kirik D, Winkler C, Bjorklund A. Growth and functional efficacy of intrastriatal nigral transplants depend on the extent of nigrostriatal degeneration.J Neurosci 21: 2889–2896, 2001.PubMedGoogle Scholar
  37. 37.
    Yurek DM, Fletcher-Turner A. Temporal changes in the neurotrophic environment of the denervated striatum as determined by the survival and outgrowth of grafted fetal dopamine neurons.Brain Res 931: 126–134, 2002.PubMedCrossRefGoogle Scholar
  38. 38.
    Carvey PM, Lin DH, Faselis CJ, Notermann JK, Ling ZD. Loss of striatal DA innervation increases striatal trophic activity directed at DA neurons in culture.Exp Neurol 140: 184–197, 1996.PubMedCrossRefGoogle Scholar
  39. 39.
    Ling ZD, Collier TJ, Sortwell CE, Lipton JW, Vu TQ, Robie HC et al. Striatal trophic activity is reduced in the aged rat brain.Brain Res 856: 301–309, 2000.PubMedCrossRefGoogle Scholar
  40. 40.
    Yurek DM, Fletcher-Turner A. Lesion-induced increase of BDNF is greater in the striatum of young versus old rat brain.Exp Neurol 161: 392–396, 2000.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhou J, Pliego-Rivero B, Bradford HF, Stern GM. The BDNF content of postnatal and adult rat brain: the effects of 6-hydroxy-dopamine lesions in adult brain.Dev Brain Res 97: 297–303, 1996.CrossRefGoogle Scholar
  42. 42.
    Yurek DM, Fletcher-Turner A. Differential expression of GDNF, BDNF, and NT-3 in the aging nigrostriatal system following a neurotoxic lesion.Brain Res 891: 228–235, 2001.PubMedCrossRefGoogle Scholar
  43. 43.
    Björklund A, Stenevi U, Schmidt RH, Dunnett SB, Gage FH. Intracerebral grafting of neuronal cell suspensions.Acta Physiol Scand Suppl 522: 1–48, 1983.PubMedGoogle Scholar
  44. 44.
    Dunnett SB, Whishaw IQ, Rogers DC, Jones GH. Dopamine-rich grafts ameliorate whole body motor asymmetry and sensory neglect but not independent limb use in rats with 6-hydroxydopamine lesions.Brain Res 415: 63–78, 1987.PubMedCrossRefGoogle Scholar
  45. 45.
    Mandel RJ, Brundin P, Bjorklund A. The importance of graft placement and task complexity for transplant-induced recovery of simple and complex sensorimotor deficits in dopamine denervated rats.Eur J Neurosci 2: 888–894, 1990.PubMedCrossRefGoogle Scholar
  46. 46.
    Annett LE, Torres EM, Ridley RM, Baker HF, Dunnett SB. A comparison of the behavioural effects of embryonic nigral grafts in the caudate nucleus and in the putamen of marmosets with unilateral 6-OHDA lesions.Exp Brain Res 103: 355–371, 1995.PubMedCrossRefGoogle Scholar
  47. 47.
    Dunnett SB, Robbins TW. The functional role of mesotelencephalic dopamine systems.Biol Rev Camb Philos Soc 67: 491–518, 1992.PubMedCrossRefGoogle Scholar
  48. 48.
    Sloan DJ, Baker BJ, Puklavec M, Charlton HM. The effect of site of transplantation and histocompatibility differences on the survival of neural tissue transplanted to the CNS of defined inbred rat strains.Prog Brain Res 82: 141–152, 1990.PubMedCrossRefGoogle Scholar
  49. 49.
    Baker-Cairns BJ, Sloan DJ, Broadwell RD, Puklavec M, Charlton HM. Contributions of donor and host blood vessels in CNS allografts.Exp Neurol 142: 36–46, 1996.PubMedCrossRefGoogle Scholar
  50. 50.
    Brundin P, Barbin G, Strecker RE, Isacson O, Prochiantz A, Bjorklund A. Survival and function of dissociated rat dopamine neurones grafted at different developmental stages or after being cultured in vitro.Brain Res 467: 233–243, 1988.PubMedGoogle Scholar
  51. 51.
    Schultzberg M, Dunnett SB, Bjorklund A, Stenevi U, Hokfelt T, Dockray GJ et al. Dopamine and cholecystokinin immunoreactive neurons in mesencephalic grafts reinnervating the neostriatum: evidence for selective growth regulation.Neuroscience 12: 17–32, 1984.PubMedCrossRefGoogle Scholar
  52. 52.
    Haque NS, LeBlanc CJ, Isacson O. Differential dissection of the rat E16 ventral mesencephalon and survival and reinnervation of the 6-OHDA-lesioned striatum by a subset of aldehyde dehydrogenase-positive TH neurons.Cell Transplant 6: 239–248, 1997.PubMedCrossRefGoogle Scholar
  53. 53.
    Isacson O, Björklund LM, Schumacher JM. Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson’s disease by stem cells.Ann Neurol 53: S135-S146, 2003.PubMedCrossRefGoogle Scholar
  54. 54.
    Hudson JL, Hoffman A, Stromberg I, Hoffer BJ, Moorhead JW. Allogeneic grafts of fetal dopamine neurons: behavioral indices of immunological interactions.Neurosci Lett 171: 32–36, 1994.PubMedCrossRefGoogle Scholar
  55. 55.
    Shinoda M, Hudson JL, Stromberg I, Hoffer BJ, Moorhead JW, Olson L. Allogeneic grafts of fetal dopamine neurons: immunological reactions following active and adoptive immunizations.Brain Res 680: 180–195, 1995.PubMedCrossRefGoogle Scholar
  56. 56.
    Shinoda M, Hudson JL, Stromberg I, Hoffer BJ, Moorhead JW, Olson L. Microglial cell responses to fetal ventral mesencephalic tissue grafting and to active and adoptive immunizations.Exp Neurol 141: 173–180, 1996.PubMedCrossRefGoogle Scholar
  57. 57.
    Duan WM, Widner H, Bjorklund A, Brundin P. Sequential intrastriatal grafting of allogeneic embryonic dopamine-rich neuronal tissue in adult rats: will the second graft be rejected?Neuroscience 57: 261–274, 1993.PubMedCrossRefGoogle Scholar
  58. 58.
    Barker RA. Repairing the brain in Parkinson’s disease: where next?Mov Disord 17: 233–241, 2002.PubMedCrossRefGoogle Scholar
  59. 59.
    Schumacher JM, Ellias SA, Palmer EP, Kott HS, Dinsmore J, Dempsey PK et al. Transplantation of embryonic porcine mesencephalic tissue in patients with PD.Neurology 54: 1042–1050, 2000.PubMedGoogle Scholar
  60. 60.
    Watts RL, Freeman TB, Hauser RA, Bakay RA, Ellias SA, Stoessl AJ et al. A double-blind, randomized, controlled, multicenter clinical trial of the safety and efficacy of stereotaxic intrastriatal implantation of fetal porcine ventral mesencephalic tissue (Neuro-cell™-PD) vs imitation surgery in patients with Parkinson’s disease (PD).Parkinsonism Relat Disord 7[Suppl]: S87, 2001.Google Scholar
  61. 61.
    Lindvall O, Kokaia Z, Martinez-Serrano A. Stem cell therapy for human neurodegenerative disorders—how to make it work.Nat Med 10[Suppl]: S42-S50, 2004.PubMedCrossRefGoogle Scholar
  62. 62.
    Björklund LM, Sanchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model.Proc Natl Acad Sci USA 99: 2344–2349, 2002.PubMedCrossRefGoogle Scholar
  63. 63.
    Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease.Nature 418: 50–56, 2002.PubMedCrossRefGoogle Scholar
  64. 64.
    Erdo F, Buhrle C, Blunk J, Hoehn M, Xia Y, Fleischmann B et al. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke.J Cereb Blood Flow Metab 23: 780–785, 2003.PubMedCrossRefGoogle Scholar
  65. 65.
    Steece-Collier K, Collier TJ, Danielson PD, Kurlan R, Yurek DM, Sladek JR Jr. Embryonic mesencephalic grafts increase levodopa-induced forelimb hyperkinesia in parkinsonian rats.Mov Disord 18: 1442–1454, 2003.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc 2004

Authors and Affiliations

  1. 1.Wallenberg Neuroscience Center and Lund Strategic Center for Stem Cell Biology and Cell TherapyBMC A11LundSweden
  2. 2.Section of Restorative Neurology, Wallenberg Neuroscience CenterBMC A11LundSweden
  3. 3.Division of Neurobiology, Wallenberg Neuroscience CenterBMC A11LundSweden

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