Cell-replacement therapies have long been an attractive prospect for treating Parkinson disease. However, the outcomes of fetal tissue-derived cell transplants in individuals with Parkinson disease have been variable, in part owing to the limitations of fetal tissue as a cell source, relating to its availability and the lack of possibility for standardization and to variation in methods. Advances in developmental and stem cell biology have allowed the development of cell-replacement therapies that comprise dopamine neurons derived from human pluripotent stem cells, which have several advantages over fetal cell-derived therapies. In this Review, we critically assess the potential trajectory of this line of translational and clinical research and address its possibilities and current limitations and the broader range of Parkinson disease features that dopamine cell replacement based on generating neurons from human pluripotent stem cells could effectively treat in the future.
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Henchcliffe, C. & Parmar, M. Repairing the brain: cell replacement using stem cell-based technologies. J. Parkinsons Dis. 8, S131–S137 (2018).
Barker, R. A., Barrett, J., Mason, S. L. & Bjorklund, A. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson’s disease. Lancet Neurol. 12, 84–91 (2013). A systematic review of transplantation trials using human fetal tissue and that includes critical reappraisal of data from the clinical trials.
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). The first protocol of bona fide hPSC-derived mesDA neurons via floorplate progenitors with good in vivo survival and functional maturation.
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).
Doi, D. et al. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation. Stem Cell Rep. 2, 337–350 (2014).
Nolbrant, S., Heuer, A., Parmar, M. & Kirkeby, A. Generation of high-purity human ventral midbrain dopaminergic progenitors for in vitro maturation and intracerebral transplantation. Nat. Protoc. 12, 1962–1979 (2017).
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). Side-by-side comparison of hESC-derived and fetal VM grafts in a preclinical model of PD demonstrated that stem cell-derived DA neurons show similar subtype-specific maturation, targeted innervation and functional potency to fetal cells.
Barker, R. A., 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 21, 569–573 (2017).
Kalia, L. V. & Lang, A. E. Parkinson’s disease. Lancet 386, 896–912 (2015).
Pagano, G. & Politis, M. Molecular imaging of the serotonergic system in Parkinson’s disease. Int. Rev. Neurobiol. 141, 173–210 (2018).
Bohnen, N. I., Kanel, P. & Muller, M. Molecular imaging of the cholinergic system in Parkinson’s disease. Int. Rev. Neurobiol. 141, 211–250 (2018).
Johnson, M. E., Stecher, B., Labrie, V., Brundin, L. & Brundin, P. Triggers, facilitators, and aggravators: redefining Parkinson’s disease pathogenesis. Trends Neurosci. 42, 4–13 (2019).
Bronstein, J. et al. Meeting report: consensus statement-Parkinson’s disease and the environment: collaborative on health and the environment and Parkinson’s action network (CHE PAN) conference 26–28 June 2007. Env. Health Perspect. 117, 117–121 (2009).
Sampson, T. The impact of indigenous microbes on Parkinson’s disease. Neurobiol. Dis. https://doi.org/10.1016/j.nbd.2019.03.014 (2019).
Billingsley, K. J., Bandres-Ciga, S., Saez-Atienzar, S. & Singleton, A. B. Genetic risk factors in Parkinson’s disease. Cell Tissue Res. 373, 9–20 (2018).
Burack, M. A. et al. In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia. Neurology 74, 77–84 (2010).
Coughlin, D. et al. Cognitive and pathological influences of tau pathology in Lewy body disorders. Ann. Neurol. 85, 259–271 (2019).
Trinh, J. et al. Genotype-phenotype relations for the Parkinson’s disease genes SNCA, LRRK2, VPS35: MDSGene systematic review. Mov. Disord. 33, 1857–1870 (2018).
Picconi, B., Hernandez, L. F., Obeso, J. A. & Calabresi, P. Motor complications in Parkinson’s disease: striatal molecular and electrophysiological mechanisms of dyskinesias. Mov. Disord. 33, 867–876 (2018).
Connolly, B. S. & Lang, A. E. Pharmacological treatment of Parkinson disease: a review. JAMA 311, 1670–1683 (2014).
Zeuner, K. E., Schaffer, E., Hopfner, F., Bruggemann, N. & Berg, D. Progress of pharmacological approaches in Parkinson’s disease. Clin. Pharmacol. Ther. 105, 1106–1120 (2019).
Martinez-Fernandez, R. et al. Focused ultrasound subthalamotomy in patients with asymmetric Parkinson’s disease: a pilot study. Lancet Neurol. 17, 54–63 (2018).
LeWitt, P. A. et al. AAV2-GAD gene therapy for advanced Parkinson’s disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 10, 309–319 (2011).
Kirik, D., Cederfjall, E., Halliday, G. & Petersen, A. Gene therapy for Parkinson’s disease: disease modification by GDNF family of ligands. Neurobiol. Dis. 97, 179–188 (2017).
Palfi, S. et al. Long-term follow-up of a phase I/II study of ProSavin, a lentiviral vector gene therapy for Parkinson’s disease. Hum. Gene Ther. Clin. Dev. 29, 148–155 (2018).
Palfi, S. et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson’s disease: a dose escalation, open-label, phase 1/2 trial. Lancet 383, 1138–1146 (2014).
Axelsen, T. M. & Woldbye, D. P. D. Gene therapy for Parkinson’s disease, an update. J. Parkinsons Dis. 8, 195–215 (2018).
Parmar, M. Towards stem cell based therapies for Parkinson’s disease. Development 145, dev156117 (2018).
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). The first description of stereotaxic implantation of human embryonic ventral mesencephalic cells in two individuals with PD. This open-label study supported further clinical transplantation trials in PD.
Lindvall, O. et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 247, 574–577 (1990).
Lindvall, O. 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).
Freed, C. R. et al. Transplantation of human fetal dopamine cells for Parkinson’s disease. Results at 1 year. Arch. Neurol. 47, 505–512 (1990).
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).
Molina, H. et al. Computer assisted CT-guided stereotactic transplantation of foetal ventral mesencephalon to the caudate nucleus and putamen in Parkinson’s disease. Acta Neurochir. Suppl. 58, 17–19 (1993).
Spencer, D. D. et al. Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson’s disease. N. Engl. J. Med. 327, 1541–1548 (1992).
Peschanski, M. et al. Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson’s disease following intrastriatal transplantation of foetal ventral mesencephalon. Brain 117, 487–499 (1994).
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).
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).
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).
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).
Farag, E. S., Vinters, H. V. & Bronstein, J. Pathologic findings in retinal pigment epithelial cell implantation for Parkinson disease. Neurology 73, 1095–1102 (2009).
Stoddard, S. L. et al. Decreased adrenal medullary catecholamines in adrenal transplanted parkinsonian patients compared to nephrectomy patients. Exp. Neurol. 104, 218–222 (1989).
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).
Hagell, P. et al. Sequential bilateral transplantation in Parkinson’s disease: effects of the second graft. Brain 122, 1121–1132 (1999).
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).
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).
Li, W. et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc. Natl Acad. Sci. USA 113, 6544–6549 (2016). Post-mortem analysis of a transplant patient 24 years after grafting showing a dense graft-derived DAergic reinnervation of the putamen and providing important proof that graft integrity can be maintained long term in a pathological environment.
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). The first report of α-synuclein-positive Lewy bodies in a subset of grafted neurons in two patients assessed after death, which, together with Kordower et al. (2008), provides the first evidence that the PD-like pathology can develop in the grafted cells. These observations also led to the still controversial theory that misfolded proteins may spread via a prion-like mechanism.
Hallett, P. J. et al. Long-term health of dopaminergic neuron transplants in Parkinson’s disease patients. Cell Rep. 7, 1755–1761 (2014).
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).
Freed, C. R. et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N. Engl. J. Med. 344, 710–719 (2001).
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).
Barker, R. A., Drouin-Ouellet, J. & Parmar, M. Cell-based therapies for Parkinson disease-past insights and future potential. Nat. Rev. Neurol. 11, 492–503 (2015).
Mendez, I. et al. Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nat. Med. 14, 507–509 (2008).
Kefalopoulou, Z. et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 71, 83–87 (2014). Long-term (15 and 18 years) follow-up of patients who received human fetal tissue transplants demonstrating sustained DA release and long-term motor improvements.
Ma, Y. et al. Dopamine cell implantation in Parkinson’s disease: long-term clinical and (18)F-FDOPA PET outcomes. J. Nucl. Med. 51, 7–15 (2010).
Piccini, P. et al. Factors affecting the clinical outcome after neural transplantation in Parkinson’s disease. Brain 128, 2977–2986 (2005).
Freeman, T. B. et al. Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson’s disease. Ann. Neurol. 38, 379–388 (1995).
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).
Liu, G. et al. Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s. Ann. Neurol. 80, 674–685 (2016).
Alcalay, R. N. et al. Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. Neurology 78, 1434–1440 (2012).
Angeli, A. et al. Genotype and phenotype in Parkinson’s disease: lessons in heterogeneity from deep brain stimulation. Mov. Disord. 28, 1370–1375 (2013).
Riboldi, G. M. & Di Fonzo, A. B. GBA, Gaucher disease, and Parkinson’s disease: from genetic to clinic to new therapeutic approaches. Cells 8, E364 (2019).
West, A. B. Achieving neuroprotection with LRRK2 kinase inhibitors in Parkinson disease. Exp. Neurol. 298, 236–245 (2017).
Sassone, J., Valtorta, F. & Ciammola, A. Early dyskinesias in Parkinson’s disease patients with parkin mutation: a primary corticostriatal synaptopathy? Front. Neurosci. 13, 273 (2019).
Barker, R. A., TRANSEURO consortium. Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease. Nat. Med. 25, 1045–1053 (2019). Description of the rationale for the design of the currently ongoing TRANSEURO trial with critical perspectives on what is to be considered when designing future stem cell-based trials.
Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
Reubinoff, B. E. et al. Neural progenitors from human embryonic stem cells. Nat. Biotechnol. 19, 1134–1140 (2001).
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).
Tao, Y. & Zhang, S. C. Neural subtype specification from human pluripotent stem cells. Cell Stem Cell 19, 573–586 (2016).
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).
Vazin, T., Chen, J., Lee, C. T., Amable, R. & Freed, W. J. Assessment of stromal-derived inducing activity in the generation of dopaminergic neurons from human embryonic stem cells. Stem Cell 26, 1517–1525 (2008).
Smith, J. R. et al. Inhibition of activin/nodal signaling promotes specification of human embryonic stem cells into neuroectoderm. Dev. Biol. 313, 107–117 (2008).
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).
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). Demonstration of rapid, synchronized and efficient neuralization of hPSCs with dual-SMAD inhibition.
Studer, L. Strategies for bringing stem cell-derived dopamine neurons to the clinic—the NYSTEM trial. Prog. Brain Res. 230, 191–212 (2017).
Steinbeck, J. A. & Studer, L. Moving stem cells to the clinic: potential and limitations for brain repair. Neuron 86, 187–206 (2015).
Kirkeby, A. et al. Predictive markers guide differentiation to improve graft outcome in clinical translation of hESC-based therapy for Parkinson’s disease. Cell Stem Cell 20, 135–148 (2017).
Chen, Y. et al. Chemical control of grafted human PSC-derived neurons in a mouse model of Parkinson’s disease. Cell Stem Cell 18, 817–826 (2016).
Kikuchi, T. et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature 548, 592–596 (2017).
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). The first demonstration of long-term survival and functional efficacy of autologous iPSC-derived DA neurons in a non-human primate model of PD.
Wakeman, D. R. et al. Cryopreservation maintains functionality of human iPSC dopamine neurons and rescues Parkinsonian phenotypes in vivo. Stem Cell Rep. 9, 149–161 (2017).
Morizane, A. et al. MHC matching improves engraftment of iPSC-derived neurons in non-human primates. Nat. Commun. 8, 385 (2017). This investigation of the effects of MHC-matched allograft and immunosuppression in non-human primates finds that MHC-matched iPSC-derived neurons provide better engraftment in the brain, with a lower immune response and higher survival of the transplanted neurons.
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).
Sundberg, M. et al. Improved cell therapy protocols for Parkinson’s disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons. Stem Cell 31, 1548–1562 (2013).
Cardoso, T. et al. Target-specific forebrain projections and appropriate synaptic inputs of hESC-derived dopamine neurons grafted to the midbrain of parkinsonian rats. J. Comp. Neurol. 526, 2133–2146 (2018).
Merkle, F. T. et al. Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations. Nature 545, 229–233 (2017).
Garitaonandia, I. et al. Increased risk of genetic and epigenetic instability in human embryonic stem cells associated with specific culture conditions. PLoS One 10, e0118307 (2015).
Amir, H. et al. Spontaneous single-copy loss of TP53 in human embryonic stem cells markedly increases cell proliferation and survival. Stem Cell 35, 872–885 (2017).
Kirkeby, A., Parmar, M. & Barker, R. A. Strategies for bringing stem cell-derived dopamine neurons to the clinic: a European approach (STEM-PD). Prog. Brain Res. 230, 165–190 (2017).
Takahashi, J. Strategies for bringing stem cell-derived dopamine neurons to the clinic: the Kyoto trial. Prog. Brain Res. 230, 213–226 (2017).
Cyranoski, D. ‘Reprogrammed’ stem cells implanted into patient with Parkinson’s disease. Nature https://doi.org/10.1038/d41586-018-07407-9 (2018).
Steinbeck, J. A. et al. Functional connectivity under optogenetic control allows modeling of human neuromuscular disease. Cell Stem Cell 18, 134–143 (2016).
Calabresi, P., Picconi, B., Tozzi, A., Ghiglieri, V. & Di Filippo, M. Direct and indirect pathways of basal ganglia: a critical reappraisal. Nat. Neurosci. 17, 1022–1030 (2014).
Lane, E. L., Bjorklund, A., Dunnett, S. B. & Winkler, C. Neural grafting in Parkinson’s disease unraveling the mechanisms underlying graft-induced dyskinesia. Prog. Brain Res. 184, 295–309 (2010).
Politis, M. et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci. Transl. Med. 2, 38ra46 (2010).
Politis, M. et al. Graft-induced dyskinesias in Parkinson’s disease: high striatal serotonin/dopamine transporter ratio. Mov. Disord. 26, 1997–2003 (2011).
Marklund, U. et al. Detailed expression analysis of regulatory genes in the early developing human neural tube. Stem Cell Dev. 23, 5–15 (2014).
Erola, T. et al. Bilateral subthalamic nucleus stimulation improves health-related quality of life in Parkinsonian patients. Parkinsonism Relat. Disord. 11, 89–94 (2005).
Rodrigues, J. P., Walters, S. E., Watson, P., Stell, R. & Mastaglia, F. L. Globus pallidus stimulation improves both motor and nonmotor aspects of quality of life in advanced Parkinson’s disease. Mov. Disord. 22, 1866–1870 (2007).
Kharkar, S. et al. Changes in Parkinson’s disease sleep symptoms and daytime somnolence after bilateral subthalamic deep brain stimulation in Parkinson’s disease. NPJ Parkinsons Dis. 4, 16 (2018).
Yang, L. et al. Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer. J. Transl. Med. 11, 107 (2013).
Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).
Daneman, R. The blood-brain barrier in health and disease. Ann. Neurol. 72, 648–672 (2012).
Sayles, M., Jain, M. & Barker, R. A. The cellular repair of the brain in Parkinson’s disease-past, present and future. Transpl. Immunol. 12, 321–342 (2004).
Kim, J. W. et al. Acute brain reaction to DBS electrodes after deep brain stimulation: chronological observation. Acta Neurochir. 155, 2365–2371; discussion 2371 (2013).
Cabezas, R. et al. Astrocytic modulation of blood brain barrier: perspectives on Parkinson’s disease. Front. Cell Neurosci. 8, 211 (2014).
Lindvall, O. et al. In reply: fetal brain grafts and Parkinson’s disease. Science 250, 1435 (1990).
Ponticelli, C. & Glassock, R. J. Prevention of complications from use of conventional immunosuppressants: a critical review. J Nephrol 32, 851–870 (2019).
Yadav, D. K., Bai, X. L. & Liang, T. Dermatological disorders following liver transplantation: an update. Can. J. Gastroenterol. Hepatol. 2019, 9780952 (2019).
Green, M. Introduction: infections in solid organ transplantation. Am. J. Transpl. 13(Suppl 4), 3–8 (2013).
Matoba, S. & Zhang, Y. Somatic cell nuclear transfer reprogramming: mechanisms and applications. Cell Stem Cell 23, 471–485 (2018).
Mandai, M. et al. Autologous induced stem-cell-derived retinal cells for macular degeneration. N. Engl. J. Med. 376, 1038–1046 (2017).
Wilmut, I. et al. Development of a global network of induced pluripotent stem cell haplobanks. Regen. Med. 10, 235–238 (2015).
Taylor, C. J., Bolton, E. M. & Bradley, J. A. Immunological considerations for embryonic and induced pluripotent stem cell banking. Philos. Trans. R. Soc. Lond. B Biol. Sci. 366, 2312–2322 (2011).
Brookhouser, N., Raman, S., Potts, C. & Brafman, D. A. May I cut in? Gene editing approaches in human induced pluripotent stem cells. Cells 6, 5 (2017).
Ben Jehuda, R., Shemer, Y. & Binah, O. Genome editing in induced pluripotent stem cells using CRISPR/Cas9. Stem Cell Rev. 14, 323–336 (2018).
Greco, R. et al. Improving the safety of cell therapy with the TK-suicide gene. Front. Pharmacol. 6, 95 (2015).
He, J., Rong, Z., Fu, X. & Xu, Y. A safety checkpoint to eliminate cancer risk of the immune evasive cells derived from human embryonic stem cells. Stem Cell 35, 1154–1161 (2017).
Zheng, D., Wang, X. & Xu, R. H. Concise review: one stone for multiple birds: generating universally compatible human embryonic stem cells. Stem Cell 34, 2269–2275 (2016).
Kordower, J. H. et al. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat. Med. 14, 504–506 (2008).
Brundin, P. & Kordower, J. H. Neuropathology in transplants in Parkinson’s disease: implications for disease pathogenesis and the future of cell therapy. Prog. Brain Res. 200, 221–241 (2012).
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).
Bieri, G. et al. LRRK2 modifies alpha-syn pathology and spread in mouse models and human neurons. Acta Neuropathol. 137, 961–980 (2019).
Beevers, J. E., Caffrey, T. M. & Wade-Martins, R. Induced pluripotent stem cell (iPSC)-derived dopaminergic models of Parkinson’s disease. Biochem. Soc. Trans. 41, 1503–1508 (2013).
Chung, S. Y. et al. Parkin and PINK1 patient iPSC-derived midbrain dopamine neurons exhibit mitochondrial dysfunction and alpha-synuclein accumulation. Stem Cell Rep. 7, 664–677 (2016).
Devine, M. J. et al. Parkinson’s disease induced pluripotent stem cells with triplication of the alpha-synuclein locus. Nat. Commun. 2, 440 (2011).
Rakovic, A., Seibler, P. & Klein, C. iPS models of parkin and PINK1. Biochem. Soc. Trans. 43, 302–307 (2015).
Sanders, L. H. et al. LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson’s disease patients: reversal by gene correction. Neurobiol. Dis. 62, 381–386 (2014).
Zambon, F. et al. Cellular alpha-synuclein pathology is associated with bioenergetic dysfunction in Parkinson’s iPSC-derived dopamine neurons. Hum. Mol. Genet. 28, 2001–2013 (2019).
Hsieh, C. H. et al. Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell 19, 709–724 (2016).
Fernandez-Santiago, R. et al. Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson’s disease patients. EMBO Mol. Med. 7, 1529–1546 (2015).
Sanchez-Danes, A. et al. Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson’s disease. EMBO Mol. Med. 4, 380–395 (2012).
Freund, T. F. et al. Efferent synaptic connections of grafted dopaminergic neurons reinnervating the host neostriatum: a tyrosine hydroxylase immunocytochemical study. J. Neurosci. 5, 603–616 (1985).
Bolam, J. P., Freund, T. F., Bjorklund, A., Dunnett, S. B. & Smith, A. D. Synaptic input and local output of dopaminergic neurons in grafts that functionally reinnervate the host neostriatum. Exp. Brain Res. 68, 131–146 (1987).
Adler, A. F. et al. hESC-derived dopaminergic transplants integrate into basal ganglia circuitry in a preclinical model of Parkinson’s disease. Cell Rep. 28, 3462–3473.e5 (2019).This study uses rabies-based monosynaptic tracing to provide a refined understanding of how graft neurons integrate with host circuitry. It shows that DAergic grafts transplanted in a long-term preclinical rat model of PD receive synaptic input from subtypes of host cortical, striatal and pallidal neurons that are known to regulate the function of endogenous nigral DA neurons.
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. 4, 975–983 (2015).
Nahimi, A. et al. Noradrenergic deficits in Parkinson disease imaged with 11C-MeNER. J. Nucl. Med. 59, 659–664 (2018).
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).
Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Parkinson’s disease is not simply a prion disorder. J. Neurosci. 37, 9799–9807 (2017).
Hall, H. et al. Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson’s disease. Brain 137, 2493–2508 (2014).
Gratwicke, J., Jahanshahi, M. & Foltynie, T. Parkinson’s disease dementia: a neural networks perspective. Brain 138, 1454–1476 (2015).
Gratwicke, J. et al. Bilateral deep brain stimulation of the nucleus basalis of meynert for Parkinson disease dementia: a randomized clinical trial. JAMA Neurol. 75, 169–178 (2018).
Garcia-Rill, E. et al. Local and relayed effects of deep brain stimulation of the pedunculopontine nucleus. Brain Sci. 9, E64 (2019).
Mills, K. A. et al. Efficacy and tolerability of antidepressants in Parkinson’s disease: a systematic review and network meta-analysis. Int. J. Geriatr. Psychiatry 33, 642–651 (2018).
Antonini, A., Moro, E., Godeiro, C. & Reichmann, H. Medical and surgical management of advanced Parkinson’s disease. Mov. Disord. 33, 900–908 (2018).
Rowland, N. C. et al. Combining cell transplants or gene therapy with deep brain stimulation for Parkinson’s disease. Mov. Disord. 30, 190–195 (2015).
Rossi, M., Bruno, V., Arena, J., Cammarota, A. & Merello, M. Challenges in PD patient management after DBS: a pragmatic review. Mov. Disord. Clin. Pract. 5, 246–254 (2018).
Combs, H. L. et al. Cognition and depression following deep brain stimulation of the subthalamic nucleus and globus pallidus pars internus in Parkinson’s disease: a meta-analysis. Neuropsychol. Rev. 25, 439–454 (2015).
Bari, A. A., Thum, J., Babayan, D. & Lozano, A. M. Current and expected advances in deep brain stimulation for movement disorders. Prog. Neurol. Surg. 33, 222–229 (2018).
Neumann, W. J. et al. Toward electrophysiology-based intelligent adaptive deep brain stimulation for movement disorders. Neurotherapeutics 16, 105–118 (2019).
Bjorklund, T., Cederfjall, E. A. & Kirik, D. Gene therapy for dopamine replacement. Prog. Brain Res. 184, 221–235 (2010).
Lindvall, O. & Bjorklund, A. Cell therapy in Parkinson’s disease. NeuroRx 1, 382–393 (2004).
Brundin, P. et al. 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).
Kelly, C. M. et al. Medical terminations of pregnancy: a viable source of tissue for cell replacement therapy for neurodegenerative disorders. Cell Transpl. 20, 503–513 (2011).
Lehnen, D. et al. IAP-based cell sorting results in homogeneous transplantable dopaminergic precursor cells derived from human pluripotent stem cells. Stem Cell Rep. 9, 1207–1220 (2017).
Daley, G. Q. et al. Setting global standards for stem cell research and clinical translation: the 2016 ISSCR guidelines. Stem Cell Rep. 6, 787–797 (2016).
Piccirillo, J. F. et al. The changing prevalence of comorbidity across the age spectrum. Crit. Rev. Oncol. Hematol. 67, 124–132 (2008).
Cummings, J. L. et al. The role of dopaminergic imaging in patients with symptoms of dopaminergic system neurodegeneration. Brain 134, 3146–3166 (2011).
Wang, Y. K. et al. Human clinical-grade parthenogenetic ESC-derived dopaminergic neurons recover locomotive defects of nonhuman primate models of Parkinson’s disease. Stem Cell Rep. 11, 171–182 (2018).
M.P. is the owner of Parmar Cells AB and co-inventor on the US patent application 15/093,927 owned by Biolamina AB, EP17181588 owned by Miltenyi Biotec and PCT/EP2018/062261 owned by New York Stem Cell Foundation. C.H. has received consultancy fees from US WorldMeds, Adamas Pharmaceuticals, Prevail Therapeutics and Mitsubishi Tanabe Pharma America.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Magnetic resonance-guided focused ultrasound ablation
An intracranial thermal ablative procedure with multiple ultrasound beams that are precisely targeted to facilitate non-incisional pallidotomy or subthalamotomy that may potentially alleviate symptoms of Parkinson disease.
- Unified Parkinson’s Disease Rating Scale
A widely used, validated clinical rating scale that evaluates non-motor symptoms, activities of daily living, motor signs and complications of levodopa therapy.
Derived from the ectoderm, the outermost of the three primary germ layers in the early embryo; its formation is the first step in development of the nervous system.
- Stromal feeder cells
Feeder cells that provide extracellular secretions to help another cell to proliferate or differentiate. Often the cells of the feeder layer are irradiated or otherwise treated to arrest growth.
- Amphetamine-induced rotation
Drug-induced turning behaviour used to assess unilateral dopaminergic lesions and effects of transplants in rodent models of Parkinson disease.
A prodrug of 1-methyl-4-phenylpyridinium, a neurotoxin leading to loss of dopamine neurons in the substantia nigra, and used to create animal models of Parkinson disease.
- Indirect pathway
A neuronal network pathway from the striatal medium spiny neurons primarily expressing dopamine D2 receptors via the globus pallidus pars externa to the subthalamic nucleus. Activation of this pathway inhibits movement and action selection. This pathway is abnormally active in Parkinson disease, as the loss of dopaminergic tone leads to disinhibition of the pathway.
- Lewy body
Abnormal intracytoplasmic protein aggregates occurring in neurons in certain neurodegenerative disorders, including Parkinson disease.
A complex intracellular process that uses hydrolytic enzymes in the lysosomes to degrade modified or damaged macromolecules and organelles.
- Corridor test
A drug-free behavioural test of lateralized neglect in animals, which is sensitive to unilateral dopamine-denervating lesions and subsequent graft-derived striatal dopaminergic replacement.
Distortion in sense of smell.
About this article
Cite this article
Parmar, M., Grealish, S. & Henchcliffe, C. The future of stem cell therapies for Parkinson disease. Nat Rev Neurosci 21, 103–115 (2020). https://doi.org/10.1038/s41583-019-0257-7