Letter | Published:

Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model

Nature volume 548, pages 592596 (31 August 2017) | Download Citation


Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson’s disease (PD), in which midbrain dopaminergic neurons progressively degenerate1,2. However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


Primary accessions

Gene Expression Omnibus


  1. 1.

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

  2. 2.

    et al. Isolation of human induced pluripotent stem cell-derived dopaminergic progenitors by cell sorting for successful transplantation. Stem Cell Reports 2, 337–350 (2014)

  3. 3.

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

  4. 4.

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

  5. 5.

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

  6. 6.

    et al. Prolonged maturation culture favors a reduction in the tumorigenicity and the dopaminergic function of human ESC-derived neural cells in a primate model of Parkinson’s disease. Stem Cells 30, 935–945 (2012)

  7. 7.

    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)

  8. 8.

    et al. LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8, 267–280 (2011)

  9. 9.

    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)

  10. 10.

    et al. Idiopathic Parkinson’s disease patient-derived induced pluripotent stem cells function as midbrain dopaminergic neurons in rodent brains. J. Neurosci. Res. 95, 1829–1837 (2017)

  11. 11.

    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)

  12. 12.

    et al. Wnt antagonism of Shh facilitates midbrain floor plate neurogenesis. Nat. Neurosci. 12, 125–131 (2009)

  13. 13.

    et al. A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc. Natl Acad. Sci. USA 94, 13305–13310 (1997)

  14. 14.

    , , , & Fail-safe therapy by gamma-ray irradiation against tumor formation by human-induced pluripotent stem cell-derived neural progenitors. Stem Cells Dev. 25, 815–825 (2016)

  15. 15.

    , , , & Comparison of eight clinical rating scales used for the assessment of MPTP-induced parkinsonism in the Macaque monkey. J. Neurosci. Methods 96, 71–76 (2000)

  16. 16.

    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)

  17. 17.

    et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J. Clin. Invest. 115, 102–109 (2005)

  18. 18.

    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)

  19. 19.

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

  20. 20.

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

  21. 21.

    et al. Signs of degeneration in 12–22-year old grafts of mesencephalic dopamine neurons in patients with Parkinson’s disease. J. Parkinsons Dis. 1, 83–92 (2011)

  22. 22.

    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)

  23. 23.

    et al. Striatal volume differences between non-human and human primates. J. Neurosci. Methods 176, 200–205 (2009)

  24. 24.

    , , & Influence of cell preparation and target location on the behavioral recovery after striatal transplantation of fetal dopaminergic neurons in a primate model of Parkinson’s disease. Neurobiol. Dis. 29, 103–116 (2008)

  25. 25.

    et al. Reference and target region modeling of [11C]-(R)-PK11195 brain studies. J. Nucl. Med. 48, 158–167 (2007)

  26. 26.

    et al. In vivo expression of cyclooxygenase-1 in activated microglia and macrophages during neuroinflammation visualized by PET with 11C-ketoprofen methyl ester. J. Nucl. Med. 52, 1094–1101 (2011)

  27. 27.

    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)

  28. 28.

    et al. Characterization of fetal antigen 1/delta-like 1 homologue expressing cells in the rat nigrostriatal system: effects of a unilateral 6-hydroxydopamine lesion. PLoS ONE 10, e0116088 (2015)

  29. 29.

    et al. Midbrain expression of Delta-like 1 homologue is regulated by GDNF and is associated with dopaminergic differentiation. Exp. Neurol. 204, 791–801 (2007)

  30. 30.

    et al. In vivo biosafety model to assess the risk of adverse events from retroviral and lentiviral vectors. Mol. Ther. 16, 1308–1315 (2008)

  31. 31.

    et al. An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord blood and peripheral blood cells. Stem Cells 31, 458–466 (2013)

  32. 32.

    et al. Laminin E8 fragments support efficient adhesion and expansion of dissociated human pluripotent stem cells. Nat. Commun. 3, 1236 (2012)

  33. 33.

    et al. A novel efficient feeder-free culture system for the derivation of human induced pluripotent stem cells. Sci. Rep. 4, 3594 (2014)

  34. 34.

    , , , & Small-molecule inhibitors of bone morphogenic protein and activin/nodal signals promote highly efficient neural induction from human pluripotent stem cells. J. Neurosci. Res. 89, 117–126 (2011)

  35. 35.

    et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23 (Suppl. 1), S208–S219 (2004)

  36. 36.

    Fast robust automated brain extraction. Hum. Brain Mapp. 17, 143–155 (2002)

  37. 37.

    & A global optimisation method for robust affine registration of brain images. Med. Image Anal. 5, 143–156 (2001)

  38. 38.

    , , & Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage 17, 825–841 (2002)

  39. 39.

    , & Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Trans. Med. Imaging 20, 45–57 (2001)

  40. 40.

    et al. An MRI based average macaque monkey stereotaxic atlas and space (MNI monkey space). Neuroimage 55, 1435–1442 (2011)

  41. 41.

    , & Hierarchical linear modeling of FIM instrument growth curve characteristics after spinal cord injury. Arch. Phys. Med. Rehabil. 82, 329–334 (2001)

  42. 42.

    , , , & Reduced midbrain dopamine transporter binding in male adolescents with attention-deficit/hyperactivity disorder: association between striatal dopamine markers and motor hyperactivity. Biol. Psychiatry 57, 229–238 (2005)

  43. 43.

    et al. Assessment of 11C-PE2I binding to the neuronal dopamine transporter in humans with the high-spatial-resolution PET scanner HRRT. J. Nucl. Med. 48, 538–546 (2007)

  44. 44.

    et al. Distribution volume ratios without blood sampling from graphical analysis of PET data. J. Cereb. Blood Flow Metab. 16, 834–840 (1996)

  45. 45.

    & Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J. Cereb. Blood Flow Metab. 5, 584–590 (1985)

  46. 46.

    , , , & Effect of dopamine loss and the metabolite 3-O-methyl-[18F]fluoro-dopa on the relation between the 18F-fluorodopa tissue input uptake rate constant Kocc and the [18F]fluorodopa plasma input uptake rate constantKi. J. Cereb. Blood Flow Metab. 23, 301–309 (2003)

Download references


We thank K. Sekiguchi, J. Toga and E. Yagi for providing recombinant LM511-E8, Y. Ono for anti-CORIN and anti-NURR1 antibodies, H. Doi, A. Mawatari, M. Tsuji, K. Takahashi, M. Goto, Y. Wada, A. Yamazaki, T. Kawasaki, C. Takeda, N. Shibata, S. Kurai, A. Igesaka, T. Mori, R. Zochi, E. Hayashinaka, M. Yamano, T. Ose, M. Ohno and K. Onoe for supporting the PET study, H. Ohmori for an electrophysiological study, S. Nolbrant for discussions about gene expression by the donor cells, and Astellas Pharma Inc. for FK506. We also thank P. Karagiannis for reading of the manuscript, K. Kubota, Y. Ishii, Y. Morita and Y. Katano for technical assistance, K. Nishimura, M. Motono, Y. Ioroi, B. Samata, Y. Koshiba, Y. Nakajima and Y. Miyawaki for taking care of the animals, and S. Tsuji, J. Mitsui and S. Morishita for whole-exome analysis of patients with PD. This study was supported by grants from the Highway Project for Realization of Regenerative Medicine from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Network Program for Realization of Regenerative Medicine from the Japan Agency for Medical Research and Development (AMED) and the Program for Intractable Diseases Research using disease-specific iPS cells from AMED (to H.I.). M.P. is a New York Stem Cell Foundation - Robertson Investigator.

Author information


  1. Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan

    • Tetsuhiro Kikuchi
    • , Asuka Morizane
    • , Daisuke Doi
    • , Hiroaki Magotani
    •  & Jun Takahashi
  2. Division of Bio-Function Dynamics Imaging, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan

    • Hirotaka Onoe
    • , Takuya Hayashi
    • , Hiroshi Mizuma
    •  & Sayuki Takara
  3. Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan

    • Ryosuke Takahashi
  4. Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan

    • Haruhisa Inoue
  5. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan

    • Satoshi Morita
    •  & Michio Yamamoto
  6. Department of Life Science Frontiers, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan

    • Keisuke Okita
    •  & Masato Nakagawa
  7. Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, 22184 Lund, Sweden

    • Malin Parmar
  8. Department of Neurosurgery, Clinical Neuroscience, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan

    • Jun Takahashi


  1. Search for Tetsuhiro Kikuchi in:

  2. Search for Asuka Morizane in:

  3. Search for Daisuke Doi in:

  4. Search for Hiroaki Magotani in:

  5. Search for Hirotaka Onoe in:

  6. Search for Takuya Hayashi in:

  7. Search for Hiroshi Mizuma in:

  8. Search for Sayuki Takara in:

  9. Search for Ryosuke Takahashi in:

  10. Search for Haruhisa Inoue in:

  11. Search for Satoshi Morita in:

  12. Search for Michio Yamamoto in:

  13. Search for Keisuke Okita in:

  14. Search for Masato Nakagawa in:

  15. Search for Malin Parmar in:

  16. Search for Jun Takahashi in:


T.K. designed the study, performed the culture, transplantation, MRI study, data analysis and interpretation, and wrote the manuscript. A.M. and D.D. assisted with cell culture, cell sorting, transplantation and the MRI study. H.Ma. generated the PD model monkeys and performed the behavioural analysis. H.O., T.H., H.Mi. and S.T. performed the PET imaging and corresponding analysis and interpretation. R.T., H.I., K.O. and M.N. generated the iPS cells. S.M. and M.Y. performed statistical analyses. M.P. provided fetal mesencephalic samples and discussed the gene expression analyses. J.T. conceived and designed the study, assembled the data, carried out the data analysis and interpretation, wrote the manuscript, and gave final approval of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jun Takahashi.

Reviewer Information Nature thanks R. Barker, A. Björklund and F. Gage for their contribution to the peer review of this work.

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

Extended data

Supplementary information

About this article

Publication history






Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.