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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.

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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


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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.

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