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  • Review Article
  • Published:

Cell-based therapies for Parkinson disease—past insights and future potential

Nature Reviews Neurology volume 11, pages 492–503 (2015)Cite this article

Subjects

Key Points

  • Dopaminergic drugs were established as an effective treatment for Parkinson disease (PD) in the 1960s, and are still the mainstay of therapy for this condition

  • Experiments that heralded the modern era of neural grafting for PD began in the 1970s in Sweden

  • Despite limited preclinical data, adrenal medullary transplantation was adopted by many groups during the 1980s, with largely disappointing results

  • Human fetal ventral mesencephalic (fVM) allografts have been shown to survive and function for over 20 years in some patients

  • The protocol for neural transplantation in patients with PD remains to be optimized

  • Human fVM grafts are currently being revisited, and stem cell-based dopamine replacement therapies are close to clinical trials

Abstract

Parkinson disease (PD) is characterized by loss of the A9 nigral neurons that provide dopaminergic innervation to the striatum. This discovery led to the successful instigation of dopaminergic drug treatments in the 1960s, although these drugs were soon recognized to lose some of their efficacy and generate their own adverse effects over time. Despite the fact that PD is now known to have extensive non-nigral pathology with a wide range of clinical features, dopaminergic drug therapies are still the mainstay of therapy, and work well for many years. Given the success of pharmacological dopamine replacement, pursuit of cell-based dopamine replacement strategies seemed to be the next logical step, and studies were initiated over 30 years ago to explore the possibility of dopaminergic cell transplantation. In this Review, we outline the history of this therapeutic approach to PD and highlight the lessons that we have learned en route. We discuss how the best clinical outcomes have been obtained with fetal ventral mesencephalic allografts, while acknowledging inconsistencies in the results owing to problems in trial design, patient selection, tissue preparation, and immunotherapy used post-grafting. We conclude by discussing the challenges of bringing the new generation of stem cell-derived dopamine cells to the clinic.

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Figure 1: Timeline of cell-based therapies for use in patients with PD.
Figure 2: Cells under consideration for use for grafting in PD.
Figure 3: Processes followed and outcomes recorded when taking different 'dopaminergic' cell sources from the laboratory to clinical trials.
Figure 4: Timeline of stem cell discoveries and their application to Parkinson disease.
Figure 5: The TRANSEURO hfVM tissue trial for the treatment of Parkinson disease.

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References

  1. Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Damier, P., Hirsch, E. C., Agid, Y. & Graybiel, A. M. The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson's disease. Brain 122, 1437–1448 (1999).

    Article  PubMed  Google Scholar 

  3. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  PubMed  Google Scholar 

  4. Jenner, P. Dopamine agonists, receptor selectivity and dyskinesia induction in Parkinson's disease. Curr. Opin. Neurol. 16 (Suppl. 1), S3–S7 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Huot, P., Johnston, T. H., Koprich, J. B., Fox, S. H. & Brotchie, J. M. The pharmacology of L-DOPA-induced dyskinesia in Parkinson's disease. Pharmacol. Rev. 65, 171–222 (2013).

    Article  CAS  PubMed  Google Scholar 

  6. Thompson, W. G. Successful brain grafting. N. Y. Med. J. 51, 701–702 (1890).

    Google Scholar 

  7. Olson, L. & Seiger, A. Brain tissue transplanted to the anterior chamber of the eye: 2. Fluorescence histochemistry of immature catecholamine- and 5-hydroxytryptamine neurons innervating the rat vas deferens. Cell Tissue Res. 158, 141–150 (1975).

    Article  CAS  PubMed  Google Scholar 

  8. Olson, L. & Seiger, A. Development and growth of immature monoamine neurons in rat and man in situ and following intraocular transplantation in the rat. Brain Res. 62, 353–360 (1973).

    Article  CAS  PubMed  Google Scholar 

  9. Olson, L. & Seiger, A. Brain tissue transplanted to the anterior chamber of the eye. 1. Fluorescence histochemistry of immature catecholamine and 5-hydroxytryptamine neurons reinnervating the rat iris. Z. Zellforsch. Mikrosk. Anat. 135, 175–194 (1972).

    Article  CAS  PubMed  Google Scholar 

  10. Barker, R. & Dunnett, S. The biology and behaviour of intracerebral adrenal transplants in animals and man. Rev. Neurosci. 4, 113–146 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Ungerstedt, U., Ljungberg, T. & Steg, G. Behavioral, physiological, and neurochemical changes after 6-hydroxydopamine-induced degeneration of the nigro-striatal dopamine neurons. Adv. Neurol. 5, 421–426 (1974).

    CAS  PubMed  Google Scholar 

  12. Ungerstedt, U. & Arbuthnott, G. W. Quantitative recording of rotational behavior in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system. Brain Res. 24, 485–493 (1970).

    Article  CAS  PubMed  Google Scholar 

  13. Ungerstedt, U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur. J. Pharmacol. 5, 107–110 (1968).

    Article  CAS  PubMed  Google Scholar 

  14. Hudson, J. L. et al. Correlation of apomorphine- and amphetamine-induced turning with nigrostriatal dopamine content in unilateral 6-hydroxydopamine lesioned rats. Brain Res. 626, 167–174 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Freed, W. J. et al. Transplanted adrenal chromaffin cells in rat brain reduce lesion-induced rotational behaviour. Nature 292, 351–352 (1981).

    Article  CAS  PubMed  Google Scholar 

  16. Perlow, M. J. et al. Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science 204, 643–647 (1979).

    Article  CAS  PubMed  Google Scholar 

  17. Hoffer, B., Freed, W., Olson, L. & Wyatt, R. J. Transplantation of dopamine-containing tissues to the central nervous system. Clin. Neurosurg. 31, 404–416 (1983).

    Article  CAS  PubMed  Google Scholar 

  18. Freed, W. J. et al. Restoration of dopaminergic function by grafting of fetal rat substantia nigra to the caudate nucleus: long-term behavioral, biochemical, and histochemical studies. Ann. Neurol. 8, 510–519 (1980).

    Article  CAS  PubMed  Google Scholar 

  19. Björklund, A., Stenevi, U., Dunnett, S. B. & Iversen, S. D. Functional reactivation of the deafferented neostriatum by nigral transplants. Nature 289, 497–499 (1981).

    Article  PubMed  Google Scholar 

  20. Björklund, A., Dunnett, S. B., Stenevi, U., Lewis, M. E. & Iversen, S. D. Reinnervation of the denervated striatum by substantia nigra transplants: functional consequences as revealed by pharmacological and sensorimotor testing. Brain Res. 199, 307–333 (1980).

    Article  PubMed  Google Scholar 

  21. Björklund, A. & Stenevi, U. Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants. Brain Res. 177, 555–560 (1979).

    Article  PubMed  Google Scholar 

  22. Björklund, A., Stenevi, U., Schmidt, R. H., Dunnett, S. B. & Gage, F. H. Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cell suspensions implanted in different brain sites. Acta Physiol. Scand. Suppl. 522, 9–18 (1983).

    PubMed  Google Scholar 

  23. Brundin, P., Barker, R. A. & Parmar, M. Neural grafting in Parkinson's disease: problems and possibilities. Prog. Brain Res. 184, 265–294 (2010).

    Article  PubMed  Google Scholar 

  24. Barker, R. A. What have open label studies of cell based therapies for Parkinson's disease told us, if anything? Basal Ganglia 4, 85–87 (2014).

    Article  Google Scholar 

  25. Backlund, E. O. et al. Transplantation of adrenal medullary tissue to striatum in parkinsonism. First clinical trials. J. Neurosurg. 62, 169–173 (1985).

    Article  CAS  PubMed  Google Scholar 

  26. Freed, W. J., Poltorak, M. & Becker, J. B. Intracerebral adrenal medulla grafts: a review. Exp. Neurol. 110, 139–166 (1990).

    Article  CAS  PubMed  Google Scholar 

  27. Madrazo, I. et al. Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson's disease. N. Engl. J. Med. 316, 831–834 (1987).

    Article  CAS  PubMed  Google Scholar 

  28. Moore, R. Y. Parkinson's disease—a new therapy? N. Engl. J. Med. 316, 872–873 (1987).

    Article  CAS  PubMed  Google Scholar 

  29. Allen, G. S., Burns, R. S., Tulipan, N. B. & Parker, R. A. Adrenal medullary transplantation to the caudate nucleus in Parkinson's disease. Initial clinical results in 18 patients. Arch. Neurol. 46, 487–491 (1989).

    Article  CAS  PubMed  Google Scholar 

  30. Drucker-Colin, R. et al. Adrenal medullary tissue transplants in the caudate nucleus of Parkinson's patients. Prog. Brain Res. 78, 567–574 (1988).

    Article  CAS  PubMed  Google Scholar 

  31. Goetz, C. G. et al. Multicenter study of autologous adrenal medullary transplantation to the corpus striatum in patients with advanced Parkinson's disease. N. Engl. J. Med. 320, 337–341 (1989).

    Article  CAS  PubMed  Google Scholar 

  32. Goetz, C. G. et al. Adrenal medullary transplant to the striatum of patients with advanced Parkinson's disease: 1-year motor and psychomotor data. Neurology 40, 273–276 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Jankovic, J. et al. Clinical, biochemical, and neuropathologic findings following transplantation of adrenal medulla to the caudate nucleus for treatment of Parkinson's disease. Neurology 39, 1227–1234 (1989).

    Article  CAS  PubMed  Google Scholar 

  34. Jiao, S. S. et al. Study of adrenal medullary tissue transplantation to striatum in parkinsonism. Prog. Brain Res. 78, 575–580 (1988).

    Article  CAS  PubMed  Google Scholar 

  35. Jiao, S. S. et al. Adrenal medullary autografts in patients with Parkinson's disease. N. Engl. J. Med. 321, 324–327 (1989).

    Article  Google Scholar 

  36. Kelly, P. J. et al. Adrenal medullary autograft transplantation into the striatum of patients with Parkinson's disease. Mayo Clin. Proc. 64, 282–290 (1989).

    Article  CAS  PubMed  Google Scholar 

  37. Lindvall, O. et al. Transplantation in Parkinson's disease: two cases of adrenal medullary grafts to the putamen. Ann. Neurol. 22, 457–468 (1987).

    Article  CAS  PubMed  Google Scholar 

  38. Ostrosky-Solis, F. et al. Neuropsychological effects of brain autograft of adrenal medullary tissue for the treatment of Parkinson's disease. Neurology 38, 1442–1450 (1988).

    Article  CAS  PubMed  Google Scholar 

  39. Goetz, C. G. et al. United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants: presurgical, and 1- and 2-year follow-up. Neurology 41, 1719–1722 (1991).

    Article  CAS  PubMed  Google Scholar 

  40. Hurtig, H., Joyce, J., Sladek, J. R. J. & Trojanowski, J. Q. Postmortem analysis of adrenal-medulla-to-caudate autograft in a patient with Parkinson's disease. Ann. Neurol. 25, 607–614 (1989).

    Article  CAS  PubMed  Google Scholar 

  41. Kompoliti, K., Chu, Y., Shannon, K. M. & Kordower, J. H. Neuropathological study 16 years after autologous adrenal medullary transplantation in a Parkinson's disease patient. Mov. Disord. 22, 1630–1633 (2007).

    Article  PubMed  Google Scholar 

  42. Kordower, J. H., Cochran, E., Penn, R. D. & Goetz, C. G. Putative chromaffin cell survival and enhanced host-derived TH-fiber innervation following a functional adrenal medulla autograft for Parkinson's disease. Ann. Neurol. 29, 405–412 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Waters, C., Itabashi, H. H., Apuzzo, M. L. & Weiner, L. P. Adrenal to caudate transplantation—postmortem study. Mov. Disord. 5, 248–250 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Lindvall, O. et al. Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up. Arch. Neurol. 46, 615–631 (1989).

    Article  CAS  PubMed  Google Scholar 

  45. Lindvall, O. et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 247, 574–577 (1990).

    Article  CAS  PubMed  Google Scholar 

  46. Brundin, P. et al. Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease. Brain 123, 1380–1390 (2000).

    Article  PubMed  Google Scholar 

  47. Lindvall, O. et al. Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson's disease. Ann. Neurol. 35, 172–180 (1994).

    Article  CAS  PubMed  Google Scholar 

  48. Wenning, G. K. et al. Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease. Ann. Neurol. 42, 95–107 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Piccini, P. et al. Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient. Nat. Neurosci. 2, 1137–1140 (1999).

    Article  CAS  PubMed  Google Scholar 

  50. Piccini, P. et al. Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts. Ann. Neurol. 48, 689–695 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Kefalopoulou, Z. et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 71, 83–87 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Freed, C. R. et al. Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N. Engl. J. Med. 327, 1549–1555 (1992).

    Article  CAS  PubMed  Google Scholar 

  53. Freeman, T. B. et al. Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease. Ann. Neurol. 38, 379–388 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Redmond, D. E. et al. Cellular replacement of dopamine deficit in Parkinson's disease using human fetal mesencephalic tissue: preliminary results in four patients. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 71, 325–359 (1993).

    PubMed  Google Scholar 

  55. Widner, H. 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).

    Article  CAS  PubMed  Google Scholar 

  56. Mendez, I. 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).

    Article  CAS  PubMed  Google Scholar 

  57. Mendez, I. 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).

    Article  PubMed  Google Scholar 

  58. Widner, H. NIH neural transplantation funding. Science 263, 737 (1994).

    Article  CAS  PubMed  Google Scholar 

  59. Kumar, R. et al. Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson's disease. Neurology 51, 850–855 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Freed, C. R. et al. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N. Engl. J. Med. 344, 710–719 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Olanow, C. W. et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann. Neurol. 54, 403–414 (2003).

    Article  PubMed  Google Scholar 

  62. Cho, C., Alterman, R., Miravite, J., Shils, J. & Tagliati, M. Subthalamic DBS for the treatment of “runaway” dyskinesias after embryonic or fetal tissue transplant. Mov. Disord. 20, 1237 (2005).

    Google Scholar 

  63. Graff-Radford, J. et al. Deep brain stimulation of the internal segment of the globus pallidus in delayed runaway dyskinesia. Arch. Neurol. 63, 1181–1184 (2006).

    Article  PubMed  Google Scholar 

  64. Herzog, J. et al. Deep brain stimulation in Parkinson's disease following fetal nigral transplantation. Mov. Disord. 23, 1293–1296 (2008).

    Article  PubMed  Google Scholar 

  65. Hagell, P. et al. Dyskinesias following neural transplantation in Parkinson's disease. Nat. Neurosci. 5, 627–628 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Ma, Y. et al. Dyskinesia after fetal cell transplantation for parkinsonism: a PET study. Ann. Neurol. 52, 628–634 (2002).

    Article  PubMed  Google Scholar 

  67. Barker, R. A. & Kuan, W. L. Graft-induced dyskinesias in Parkinson's disease: what is it all about? Cell Stem Cell 7, 148–149 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Politis, M. et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. Sci. Transl. Med. 2, 38ra46 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Politis, M. et al. Graft-induced dyskinesias in Parkinson's disease: high striatal serotonin/dopamine transporter ratio. Mov. Disord. 26, 1997–2003 (2011).

    Article  PubMed  Google Scholar 

  70. Lane, E. L., Winkler, C., Brundin, P. & Cenci, M. A. 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 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Winkler, C., Georgievska, B., Carlsson, T., Lacar, B. & Kirik, D. Continuous exposure to glial cell line-derived neurotrophic factor to mature dopaminergic transplants impairs the graft's ability to improve spontaneous motor behavior in parkinsonian rats. Neuroscience 141, 521–531 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Mendez, I. et al. 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 (2005).

    Article  PubMed  Google Scholar 

  73. Krack, P., Poepping, M., Weinert, D., Schrader, B. & Deuschl, G. Thalamic, pallidal, or subthalamic surgery for Parkinson's disease? J. Neurol. 247 (Suppl. 2), II122–II134 (2000).

    PubMed  Google Scholar 

  74. Ma, Y. et al. Dopamine cell implantation in Parkinson's disease: long-term clinical and 18F-FDOPA PET outcomes. J. Nucl. Med. 51, 7–15 (2010).

    Article  PubMed  Google Scholar 

  75. Barker, R. A., Barrett, J., Mason, S. L. & Björklund, A. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson's disease. Lancet Neurol. 12, 84–91 (2013).

    Article  CAS  PubMed  Google Scholar 

  76. Piccini, P. et al. Factors affecting the clinical outcome after neural transplantation in Parkinson's disease. Brain 128, 2977–2986 (2005).

    Article  PubMed  Google Scholar 

  77. Kordower, J. H. 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).

    Article  CAS  PubMed  Google Scholar 

  78. Kordower, J. H. 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).

    Article  CAS  PubMed  Google Scholar 

  79. Kordower, J. H. et al. Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease. Mov. Disord. 13, 383–393 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. TRANSEURO [online], (2014).

  81. Barker, R. A., Kendall, A. L. & Widner, H. Neural tissue xenotransplantation: what is needed prior to clinical trials in Parkinson's disease? Neural Tissue Xenografting Project. Cell Transplant. 9, 235–246 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Galpern, W. R., Burns, L. H., Deacon, T. W., Dinsmore, J. & Isacson, O. Xenotransplantation of porcine fetal ventral mesencephalon in a rat model of Parkinson's disease: functional recovery and graft morphology. Exp. Neurol. 140, 1–13 (1996).

    Article  CAS  PubMed  Google Scholar 

  83. Schumacher, J. M. et al. Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology 54, 1042–1050 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Arjona, V. et al. Autotransplantation of human carotid body cell aggregates for treatment of Parkinson's disease. Neurosurgery 53, 321–328 (2003).

    Article  PubMed  Google Scholar 

  85. Minguez-Castellanos, A. et al. Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study. J. Neurol. Neurosurg. Psychiatry 78, 825–831 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Bakay, R. A. et al. Implantation of Spheramine in advanced Parkinson's disease (PD). Front. Biosci. 9, 592–602 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Stover, N. P. et al. Intrastriatal implantation of human retinal pigment epithelial cells attached to microcarriers in advanced Parkinson disease. Arch. Neurol. 62, 1833–1837 (2005).

    Article  PubMed  Google Scholar 

  88. Stover, N. P. & Watts, R. L. Spheramine for treatment of Parkinson's disease. Neurotherapeutics 5, 252–259 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Watts, R. L. et al. Stereotaxic intrastriatal implantation of human retinal pigment epithelial (hRPE) cells attached to gelatin microcarriers: a potential new cell therapy for Parkinson's disease. J. Neural Transm. Suppl. 65, 215–227 (2003).

    Article  Google Scholar 

  90. Gross, R. E. et al. Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol. 10, 509–519 (2011).

    Article  PubMed  Google Scholar 

  91. Ribeiro, D. et al. Efficient expansion and dopaminergic differentiation of human fetal ventral midbrain neural stem cells by midbrain morphogens. Neurobiol. Dis. 49, 118–127 (2013).

    Article  CAS  PubMed  Google Scholar 

  92. Barker, R. A. & de Beaufort, I. Scientific and ethical issues related to stem cell research and interventions in neurodegenerative disorders of the brain. Prog. Neurobiol. 110, 63–73 (2013).

    Article  PubMed  Google Scholar 

  93. Barker, R. A. Developing stem cell therapies for Parkinson's disease: waiting until the time is right. Cell Stem Cell 15, 539–542 (2014).

    Article  CAS  PubMed  Google Scholar 

  94. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Reubinoff, B. E., Pera, M. F., Fong, C. Y., Trounson, A. & Bongso, A. Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat. Biotechnol. 18, 399–404 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Itskovitz-Eldor, J. et al. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol. Med. 6, 88–95 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Reubinoff, B. E. et al. Neural progenitors from human embryonic stem cells. Nat. Biotechnol. 19, 1134–1140 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Zhang, S. C., Wernig, M., Duncan, I. D., Brustle, O. & Thomson, J. A. In vitro differentiation of transplantable neural precursors from human embryonic stem cells. Nat. Biotechnol. 19, 1129–1133 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Kawasaki, H. et al. Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 28, 31–40 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Kim, J. H. et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50–56 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Brederlau, A. 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 24, 1433–1440 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Park, C. H. et al. In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J. Neurochem. 92, 1265–1276 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. Perrier, A. L. et al. Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc. Natl Acad. Sci. USA 101, 12543–12548 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sonntag, K. C. et al. Enhanced yield of neuroepithelial precursors and midbrain-like dopaminergic neurons from human embryonic stem cells using the bone morphogenic protein antagonist noggin. Stem Cells 25, 411–418 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Zeng, X. et al. Dopaminergic differentiation of human embryonic stem cells. Stem Cells 22, 925–940 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Roy, N. S. et al. Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat. Med. 12, 1259–1268 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Cooper, O. et al. Differentiation of human ES and Parkinson's disease iPS cells into ventral midbrain dopaminergic neurons requires a high activity form of SHH, FGF8a and specific regionalization by retinoic acid. Mol. Cell. Neurosci. 45, 258–266 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Yan, Y. et al. Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells. Stem Cells 23, 781–790 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yang, D., Zhang, Z. J., Oldenburg, M., Ayala, M. & Zhang, S. C. Human embryonic stem cell-derived dopaminergic neurons reverse functional deficit in parkinsonian rats. Stem Cells 26, 55–63 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Takahashi, K., Okita, K., Nakagawa, M. & Yamanaka, S. Induction of pluripotent stem cells from fibroblast cultures. Nat. Protoc. 2, 3081–3089 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Soldner, F. et al. Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 136, 964–977 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hargus, G. et al. Differentiated Parkinson patient-derived induced pluripotent stem cells grow in the adult rodent brain and reduce motor asymmetry in parkinsonian rats. Proc. Natl Acad. Sci. USA 107, 15921–15926 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Kikuchi, T. et al. Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson's disease. J. Parkinsons Dis. 1, 395–412 (2011).

    CAS  PubMed  Google Scholar 

  114. Bonilla, S. et al. Identification of midbrain floor plate radial glia-like cells as dopaminergic progenitors. Glia 56, 809–820 (2008).

    Article  PubMed  Google Scholar 

  115. Ono, Y. et al. Differences in neurogenic potential in floor plate cells along an anteroposterior location: midbrain dopaminergic neurons originate from mesencephalic floor plate cells. Development 134, 3213–3225 (2007).

    Article  CAS  PubMed  Google Scholar 

  116. Placzek, M. & Briscoe, J. The floor plate: multiple cells, multiple signals. Nat. Rev. Neurosci. 6, 230–240 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Arenas, E., Denham, M. & Villaescusa, J. C. How to make a midbrain dopaminergic neuron. Development 142, 1918–1936 (2015).

    Article  CAS  PubMed  Google Scholar 

  118. Chambers, S. M. et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 27, 275–280 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tabar, V. & Studer, L. Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat. Rev. Genet. 15, 82–92 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Fasano, C. A., Chambers, S. M., Lee, G., Tomishima, M. J. & Studer, L. Efficient derivation of functional floor plate tissue from human embryonic stem cells. Cell Stem Cell 6, 336–347 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Kirkeby, A. et al. Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions. Cell Rep. 1, 703–714 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Kriks, S. et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature 480, 547–551 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Grealish, S. et al. Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease. Cell Stem Cell 15, 653–665 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Grealish, S. et al. Monosynaptic tracing using modified rabies virus reveals early and extensive circuit integration of human embryonic stem cell-derived neurons. Stem Cell Rep. http://dx.doi.org/10.1016/j.stemcr.2015.04.011.

  125. Steinbeck, J. A. et al. Optogenetics enables functional analysis of human embryonic stem cell-derived grafts in a Parkinson's disease model. Nat. Biotechnol. 33, 204–209 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Rath, A. et al. Survival and functional restoration of human fetal ventral mesencephalon following transplantation in a rat model of Parkinson's disease. Cell Transplant. 22, 1281–1293 (2013).

    Article  PubMed  Google Scholar 

  127. Alper, J. Geron gets green light for human trial of ES cell-derived product. Nat. Biotechnol. 27, 213–214 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Kanemura, H. et al. Tumorigenicity studies of induced pluripotent stem cell (iPSC)-Derived retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration. PLoS ONE 9, e85336 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat. Med. 14, 504–506 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat. Med. 14, 501–503 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Chu, Y. & Kordower, J. H. Lewy body pathology in fetal grafts. Ann. N. Y. Acad. Sci. 1184, 55–67 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Li, J. Y. et al. Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease. Mov. Disord. 25, 1091–1096 (2010).

    Article  PubMed  Google Scholar 

  133. Guo, J. L. & Lee, V. M. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases. Nat. Med. 20, 130–138 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Hallett, P. J. et al. Long-term health of dopaminergic neuron transplants in Parkinson's disease patients. Cell Rep. 7, 1755–1761 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Abbott, A. Fetal-cell revival for Parkinson's. Nature 510, 195–196 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. GForce-PD [online], (2015).

  137. Hirsch, E. C., Duyckaerts, C., Javoy-Agid, F., Hauw, J. J. & Agid, Y. Does adrenal graft enhance recovery of dopaminergic neurons in Parkinson's disease? Ann. Neurol. 27, 676–682 (1990).

    Article  CAS  PubMed  Google Scholar 

  138. Peterson, D. I., Price, M. L. & Small, C. S. Autopsy findings in a patient who had an adrenal-to-brain transplant for Parkinson's disease. Neurology 39, 235–238 (1989).

    Article  CAS  PubMed  Google Scholar 

  139. Olanow, C. W. et al. Autologous transplantation of adrenal medulla in Parkinson's disease. 18-month results. Arch. Neurol. 47, 1286–1289 (1990).

    Article  CAS  PubMed  Google Scholar 

  140. Hallett, P. J. et al. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease. Cell Stem Cell 16, 269–274 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Delcroix, G. J. et al. The therapeutic potential of human multipotent mesenchymal stromal cells combined with pharmacologically active microcarriers transplanted in hemi-parkinsonian rats. Biomaterials 32, 1560–1573 (2011).

    Article  CAS  PubMed  Google Scholar 

  142. Offen, D. et al. Intrastriatal transplantation of mouse bone marrow-derived stem cells improves motor behavior in a mouse model of Parkinson's disease. J. Neural Transm. Suppl. 133–143 (2007).

  143. Sanchez-Pernaute, R., Studer, L., Bankiewicz, K. S., Major, E. O. & McKay, R. D. In vitro generation and transplantation of precursor-derived human dopamine neurons. J. Neurosci. Res. 65, 284–288 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Caiazzo, M. et al. Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476, 224–227 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Pfisterer, U. et al. Direct conversion of human fibroblasts to dopaminergic neurons. Proc. Natl Acad. Sci. USA 108, 10343–10348 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors' own work is supported by grants from Neurostemcellrepair (grant no. 602278) and the Swedish Research Council (grants K2012-99X-22324-01-5 and K2014-61X-20391-08-4) and TRANSEURO, and by the National institute for Health Research (NIHR)-funded Biomedical Research Centre in Cambridge, UK. M.P. is funded from the European Research Council ERC Grant Agreement no. 309712. We would also like to thank Hakan Widner, Olle Lindvall and Anders Björklund for their advice and input, especially relating to information on the patients grafted in Lund.

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  1. John van Geest Centre for Brain Repair & Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, CB2 0PY, Cambridge, UK

    Roger A. Barker

  2. Division of Neurobiology and Lund Stem Cell Center, Wallenberg Neuroscience Center, Lund University, BMC A11, S-221 84, Lund, Sweden

    Janelle Drouin-Ouellet & Malin Parmar

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  1. Roger A. Barker
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All authors researched data for the article and reviewed and/or edited the manuscript before submission. R.A.B. and M.P. discussed the content and wrote the article.

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Barker, R., Drouin-Ouellet, J. & Parmar, M. Cell-based therapies for Parkinson disease—past insights and future potential. Nat Rev Neurol 11, 492–503 (2015). https://doi.org/10.1038/nrneurol.2015.123

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