Cell therapy for Parkinson′s disease is coming of age: current challenges and future prospects with a focus on immunomodulation

Abstract

Parkinson’s disease (PD) is a neurodegenerative disease that affects more than 1% of people over the age of 60. The principal feature of this disease is the progressive loss of dopaminergic neurons (DAn) within the nigrostriatal system, causing the motor symptoms observed in these patients. At present, there is no therapeutic approach with a cytoprotective effect that can prevent DAn cell death or disease progression. Cell replacement therapy began 30 years ago with the objective to compensate for the loss of DAn by transplantation of dopamine-producing cells. The results from these trials have provided proof of concept of safety and efficacy of cell replacement. However, a major limiting factor of this strategy has been the poor survival rate of grafted DAn. An important factor that could cause cell death of DA precursors is the host response to the graft. In this review, we discuss the factors that affect the outcome of cell therapy in PD, with focus on the cell types used and the functional effects of the host immune response on graft survival and differentiation. We also discuss the strategies that may increase the efficacy of cell replacement therapy which target the host immune response.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. 1.

    Lesage S, Brice A. Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet. 2009;18(R1):R48–59.

    CAS  PubMed  Google Scholar 

  2. 2.

    Obeso JA, Rodriguez-Oroz MC, Goetz CG, Marin C, Kordower JH, Rodriguez M, et al. Missing pieces in the Parkinson’s disease puzzle. Nat Med. 2010;16:653–61.

    CAS  PubMed  Google Scholar 

  3. 3.

    Coelho M, Ferreira JJ. Late-stage Parkinson disease. Nat Rev Neurol. 2012;8:435–42.

    CAS  PubMed  Google Scholar 

  4. 4.

    Hassanzadeh K, Rahimmi A. Oxidative stress and neuroinflammation in the story of Parkinson’s disease: Could targeting these pathways write a good ending? J Cell Physiol. 2018;234:23–32.

    PubMed  Google Scholar 

  5. 5.

    GBD 2015 Neurological Disorders Collaborator Group. Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 2017;16:877–97.

    Google Scholar 

  6. 6.

    Dorsey ER, Bloem BR. The Parkinson pandemic—a call to action. JAMA Neurol. 2018;75:9–10.

    PubMed  Google Scholar 

  7. 7.

    Wenker SD, Leal MC, Farías MI, Zeng X, Pitossi FJ. Cell therapy for Parkinson’s disease: Functional role of the host immune response on survival and differentiation of dopaminergic neuroblasts. Brain Res. 2016;1638:15–29.

    CAS  PubMed  Google Scholar 

  8. 8.

    Valldeoriola F, Puig-Junoy J, Puig-Peiró R. Workgroup of the SCOPE study. Cost analysis of the treatments for patients with advanced Parkinson’s disease: SCOPE study. J Med Econ. 2013;16:191–201.

    PubMed  Google Scholar 

  9. 9.

    Gardner J. A history of deep brain stimulation: technological innovation and the role of clinical assessment tools. Soc Stud Sci. 2013;43:707–28.

    PubMed Central  Google Scholar 

  10. 10.

    Fawcett JW. Death and survival in CNS Grafting. In: Dunnett SB, Boulton AA, Baker GB, eds. Neural transplantation methods. Humana Press Inc., Totowa, NJ. United States; 2000. pp 441–60.

    Google Scholar 

  11. 11.

    Björklund A, Stenevi U. Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants. Brain Res. 1979;177:555–60.

    PubMed  Google Scholar 

  12. 12.

    Björklund A, Schmidt RH, Stenevi U. Functional reinnervation of the neostriatum in the adult rat by use of intraparenchymal grafting of dissociated cell suspensions from the substancia nigra. Cell Tissue Res. 1980;212:39–45.

    PubMed  Google Scholar 

  13. 13.

    McGuire P, Strecker RE, Widner H, Clarke DJ, Nilsson OG, Astedt B, et al. Human fetal dopamine neurons grafted in a rat model of Parkinson′s disease: immunological aspects, spontaneous and drug induced behaviour, and dopamine release. Exp Brain Res. 1988;70:192–208.

    Google Scholar 

  14. 14.

    Wijeyekoon R, Barker RA. Cell replacement therapy for Parkinson’s disease. Biochim Biophys Acta. 2009;1792:688–702.

    CAS  PubMed  Google Scholar 

  15. 15.

    Björklund A, Lindvall O. Replacing Dopamine neurons in Parkinson’s disease: how did it happen? J Parkinsons Dis. 2017;7(s1):S21–S31.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Lindvall O, Björklund A. Cell therapeutics in Parkinson’s disease. Neurotherapeutics. 2011;8:539–48.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Barker RA, Barrett J, Mason SL, Bjorklund A. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson’s disease. The Lancet Neurology. 2013;12:84–91.

    CAS  PubMed  Google Scholar 

  18. 18.

    Lindvall O. Developing dopaminergic cell therapy for Parkinson’s disease—give up or move forward? Mov Disord. 2013;28:268–73.

    CAS  PubMed  Google Scholar 

  19. 19.

    Breysse N, Carlsson T, Winkler C, Björklund A, Kirik D. The functional impact of the intrastriatal dopamine neuron grafts in parkinsonian rats is reduced with advancing disease. J Neurosci. 2007;27:5849–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Moore SF, Guzman NV, Mason SL, Williams-Gray CH, Barker RA. Which patients with Parkinson’s disease participate in clinical trials? One centre’s experiences with a new cell based therapy trial (TRANSEURO). J. Parkinsons Dis. 2014;4:671–6.

    PubMed  Google Scholar 

  21. 21.

    Barker RA, Studer L, Cattaneo E, Takahashi J, G-Force PD. consortium. G-Force PD: a global initiative in coordinating stem cell-based dopamine treatments for Parkinson’s disease. NPJ Parkinsons Dis. 2015;1:15017.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Fjodorova M, Torres EM, Dunnett SB. Transplantation site influences the phenotypic differentiation of dopamine neurons in ventral mesencephalic grafts in Parkinsonian rats. Exp Neurol. 2017;291:8–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Barker RA, Parmar M, Studer L, Takahashi J. Human trials of stem cell-derived dopamine neurons for Parkinson’s disease: dawn of a new era. Cell Stem Cell. 2017;21:569–73.

    CAS  PubMed  Google Scholar 

  24. 24.

    Sonntag KC, Song B, Lee N, Jung JH, Cha Y, Leblanc P, et al. Pluripotent stem cell-based therapy for Parkinson’s disease: current status and future prospects. Prog Neurobiol. 2018;168:1–20.

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Stoker TB, Barker RA. Cell therapies for Parkinson’s disease: how far have we come? Regen Med. 2016;11:777–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Kim J, Su SC, Wang H, Cheng AW, Cassady JP, Lodato MA, et al. Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell. 2011;4;9:413–9.

    Google Scholar 

  27. 27.

    Parmar M. Towards stem cell-based therapies for Parkinson’s disease. Development. 2018. https://doi.org/10.1242/dev.156117.

    PubMed  Google Scholar 

  28. 28.

    Takahashi J. Strategies for bringing stem cell-derived dopamine neurons to the clinic: The Kyoto trial. Prog Brain Res. 2017;230:213–26.

    PubMed  Google Scholar 

  29. 29.

    Turner M, Leslie S, Martin NG, Peschanski M, Rao M, Taylor CJ, et al. Toward the development of a global induced pluripotent stem cell library. Cell Stem Cell. 2013;13:382–4.

    CAS  PubMed  Google Scholar 

  30. 30.

    Solomon S, Pitossi F, Rao MS. Banking on iPSC—is it doable and is it worthwhile. Stem Cell Rev. 2015;11:1–10.

    CAS  Google Scholar 

  31. 31.

    Brundin P, Karlsson J, Emgård M, Schierle GS, Hansson O, Petersén A, et al. Improving the survival of grafted dopaminergic neurons: a review over current approaches. Cell Transplant. 2000;9:179–95.

    CAS  PubMed  Google Scholar 

  32. 32.

    Sortwell CE, Pitzer MR, Collier TJ. Time course of apoptotic cell death within mesencephalic cell suspension grafts: implications for improving grafted dopamine neuron survival. Exp Neurol. 2000;165:268–77.

    CAS  PubMed  Google Scholar 

  33. 33.

    Duan WM, Westerman M, Flores T, Low WC. Survival of intrastriatal xenografts of ventral mesencephalic dopamine neurons from MHC-deficient mice to adult rats. Exp Neurol. 2001;167:108–17.

    CAS  PubMed  Google Scholar 

  34. 34.

    Duan WM, Westerman MA, Wong G, Low WC. Rat nigral xenografts survive in the brain of MHC class II-, but not class I-deficient mice. Neuroscience. 2002;115:495–504.

    CAS  PubMed  Google Scholar 

  35. 35.

    Duan WM, Widner H, Brundin P. Temporal pattern of host responses against intrastriatal grafts of syngeneic, allogeneic or xenogeneic embryonic neuronal tissue in rats. Exp Brain Res. 1995;104:227–42.

    CAS  PubMed  Google Scholar 

  36. 36.

    Brundin P, Nilsson OG, Gage FH, Bjorklund A. Cyclosporin A increases survival of cross-species intrastriatal grafts of embryonic dopamine-containing neurons. Exp Brain Res. 1985;60:204–8.

    CAS  PubMed  Google Scholar 

  37. 37.

    Galpern WR, Burns LH, Deacon TW, 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. 1996;140:1–13.

    CAS  PubMed  Google Scholar 

  38. 38.

    Larsson LC, Czech KA, Brundin P, Widner H. Intrastriatal ventral mesencephalic xenografts of porcine tissue in rats: immune responses and functional effects. Cell Transplant. 2000;9:261–72.

    CAS  PubMed  Google Scholar 

  39. 39.

    Larsson LC, Frielingsdorf H, Mirza B, Hansson SJ, Anderson P, Czech KA, et al. Porcine neural xenografts in rats and mice: donor tissue development and characteristics of rejection. Exp Neurol. 2001;172:100–14.

    CAS  PubMed  Google Scholar 

  40. 40.

    Kriks S, Shim JW, Piao J, Ganat YM, Wakeman DR, Xie Z, et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature. 2011;480:547–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Emborg ME, Liu Y, Xi J, Zhang X, Yin Y, Lu J, et al. Induced pluripotent stem cell-derived neural cells survive and mature in the nonhuman primate brain. Cell Rep. 2013a;3:646–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Emborg ME, Zhang Z, Joers V, Brunner K, Bondarenko V, Ohshima S, et al. Intracerebral transplantation of differentiated human embryonic stem cells to hemiparkinsonian monkeys. Cell Transplant. 2013b;22:831–8.

    PubMed  Google Scholar 

  43. 43.

    Ideguchi M, Shinoyama M, Gomi M, Hayashi H, Hashimoto N, Takahashi J. Immune or inflammatory response by the host brain suppresses neuronal differentiation of transplanted ES cell-derived neural precursor cells. J Neurosci Res. 2008;86:1936–43.

    CAS  PubMed  Google Scholar 

  44. 44.

    Hoornaert CJ, Le Blon D, Quarta A, Daans J, Goossens H, Berneman Z, et al. Concise review: innate and adaptive immune recognition of allogeneic and xenogeneic cell transplants in the central nervous system. Stem Cells Transl Med. 2017;6:1434–41.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Kikuchi T, Morizane A, Doi D, Magotani H, Onoe H, Hayashi T, et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature. 2017;548:592–6.

    CAS  Google Scholar 

  46. 46.

    Reekmans K, De Vocht N, Praet J, Fransen E, Le Blon D, Hoornaert C, et al. Spatiotemporal evolution of early innate immune responses triggered by neural stem cell grafting. Stem Cell Res Ther. 2012;3:56.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Praet J, Santermans E, Daans J, Le Blon D, Hoornaert C, Goossens H, et al. Early inflammatory responses following cell grafting in the CNS trigger activation of the subventricular zone: a proposed model of sequential cellular events. Cell Transplant. 2015;24:1481–92.

    PubMed  Google Scholar 

  48. 48.

    Tomov N, Surchev L, Wiedenmann C, Döbrössy MD, Nikkhah G. Astrogliosis has different dynamics after cell transplantation and mechanical impact in the rodent model of Parkinson′s disease. Balkan Med J. 2018;35:141–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Morizane A, Kikuchi T, Hayashi T, Mizuma H, Takara S, Doi H, et al. MHC matching improves engraftment of iPSC-derived neurons in non-human primates. Nat Commun. 2017;8:385.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Soderstrom KE, Meredith G, Freeman TB, McGuire SO, Collier TJ, Sortwell CE, et al. The synaptic impact of the host immune response in a parkinsonian allograft model rat model: Influence on graft-derived aberrant behaviors. Neurobiol Dis. 2008;32:229–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Steece-Collier K, Soderstrom KE, Collier TJ, Sortwell CE, Maries-Lad E. Effect of levodopa priming on dopamine neuron transplant efficacy and induction of abnormal involuntary movements in parkinsonian rats. J Comp Neurol. 2009;515:15–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Clarke DJ, Branton RL. A role for tumor necrosis factor alpha in death of dopaminergic neurons following neural transplantation. Exp Neurol. 2001;176:154–62.

    Google Scholar 

  53. 53.

    McGuire SO, Ling ZD, Lipton JW, Sortwell CE, Collier TJ, Carvey PM. Tumor necrosis factor alpha is toxic to embryonic mesencephalic dopamine neurons. Exp Neurol. 2001;169:219–30.

    CAS  PubMed  Google Scholar 

  54. 54.

    Breger LS, Kienle K, Smith GA, Dunnett SB, Lane EL. Influence of chronic L-DOPA treatment on immune response following allogeneicand xenogeneic graft in a rat model of Parkinson’s disease. Brain Behav Immun. 2017;61:155–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Horrocks LA, Yeo YK. Health benefits of docosahexaenoic acid (DHA). Pharmacol Res. 1999;40:211–25.

    CAS  PubMed  Google Scholar 

  56. 56.

    Bazan NG. Docosanoids and elovanoids from omega-3 fatty acids are pro-homeostatic modulators of inflammatory responses, cell damage and neuroprotection. Mol Aspects Med. 2018;64:18–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Chang YL, Chen SJ, Kao CL, Hung SC, Ding DC, Yu CC, et al. Docosahexaenoic acid promotes dopaminergic differentiation in inducedpluripotent stem cells and inhibits teratoma formation in rats with Parkinson-likepathology. Cell Transplant. 2012;21:313–32.

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    He XB, Kim M, Kim SY, Yi SH, Rhee YH, Kim T, et al. Vitamin C facilitates dopamine neuron differentiation in fetal midbrain through TET1 and JMJD3-dependent epigenetic control manner. Stem Cells. 2015;33:1320–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Wulansari N, Kim EH, Sulistio YA, Rhee YH, Song JJ, Lee SH. Vitamin C-induced epigenetic modifications in donor NSCs establish midbrain marker expressions critical for cell-based therapy in Parkinson’s disease. Stem Cell Rep. 2017;9:1192–206.

    CAS  Google Scholar 

  60. 60.

    Rodriguez-Pallares J, Rodriguez-Perez AI, Muñoz A, Parga JA, Toledo-Aral JJ, Labandeira-Garcia JL. Effects of Rho kinase inhibitors of grafts of dopaminergic cell precursors in a rat model of Parkinson’s disease. Stem Cells Transl Med. 2016;5:804–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Moriarty N, Cabré S, Alamilla V, Pandit A, Dowd E. Encapsulation of young donor age dopaminergic grafts in a GDNF-loaded collagen hydrogel further increases their survival, reinnervation, and functional efficacy after intrastriatal transplantation in hemi-Parkinsonian rats. Eur J Neurosci. 2018. https://doi.org/10.1111/ejn.14090.

    PubMed  Google Scholar 

  62. 62.

    Adil MM, Vazin T, Ananthanarayanan B, Rodrigues GMC, Rao AT, Kulkarni RU, et al. Engineered hydrogels increase the post-transplantation survival of encapsulated hESC-derived midbrain dopaminergic neurons. Biomaterials. 2017;136:1–11.

    CAS  PubMed  Google Scholar 

  63. 63.

    Moriarty N, Pandit A, Dowd E. Encapsulation of primary dopaminergic neurons in a GDNF-loaded collagen hydrogel increases their survival, reinnervation and function after intra-striatal transplantation. Sci Rep. 2017;7:16033.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Furlanetti LL, Cordeiro JG, Cordeiro KK, García JA, Winkler C, Lepski GA, et al. Continuous high-frequency stimulation of the subthalamic nucleus improves cell survival and functional recovery following dopaminergic cell transplantation in rodents. Neurorehabil Neural Repair. 2015;29:1001–12.

    PubMed  Google Scholar 

  65. 65.

    Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Rehncrona S, et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci Transl Med. 2010;2:38ra46.

    PubMed  Google Scholar 

  66. 66.

    Politis M, Wu K, Loane C, Brooks DJ, Kiferle L, Turkheimer FE, et al. Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson′s disease patients. J Clin Invest. 2014;124:1340–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Kirkeby A, Parmar M, Barker RA. Strategies for bringing stem cell-derived dopamine neurons to the clinic: a European approach (STEM-PD). Prog Brain Res. 2017;230:165–90.

    PubMed  Google Scholar 

  68. 68.

    Parmar M, Torper O, Drouin-Ouellet J. Cell-based therapy for Parkinson’s disease: A journey through decades towards the light side of the Force. Eur J Neurosci. 2018. https://doi.org/10.1111/ejn.14109.

    PubMed  Google Scholar 

  69. 69.

    Studer L. Strategies for bringing stem cell-derived dopamine neurons to the clinic-The NYSTEM trial. Prog Brain Res. 2017;230:191–212.

    PubMed  Google Scholar 

  70. 70.

    Peng J, Liu Q, Rao MS, Zeng X. Survival and engraftment of dopaminergic neurons manufactured by a Good Manufacturing Practice-compatible process. Cytotherapy. 2014;16:1305–12.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

SDW and FJP are members of the research career of CONICET.

Funding

National Agency for Scientific and Technologic Promotion (ANPCYT, Argentina), National Scientific and Technical Research Council (CONICET, Argentina).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Fernando J. Pitossi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wenker, S.D., Pitossi, F.J. Cell therapy for Parkinson′s disease is coming of age: current challenges and future prospects with a focus on immunomodulation. Gene Ther 27, 6–14 (2020). https://doi.org/10.1038/s41434-019-0077-4

Download citation

Further reading

Search

Quick links