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

Kikuchi, Tetsuhiro; Morizane, Asuka LU ; Doi, Daisuke; Magotani, Hiroaki; Onoe, Hirotaka; Hayashi, Takuya; Mizuma, Hiroshi; Takara, Sayuki; Takahashi, Ryosuke and Inoue, Haruhisa, et al. (2017) In Nature 548(7669). p.592-596
Abstract

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 degenerate. 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... (More)

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 degenerate. 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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published
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Nature
volume
548
issue
7669
pages
5 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85028718550
  • wos:000408703100040
ISSN
0028-0836
DOI
10.1038/nature23664
language
English
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yes
id
991a59ec-531d-46dd-80c5-01e928e403eb
date added to LUP
2017-10-06 10:13:57
date last changed
2018-10-21 04:50:50
@article{991a59ec-531d-46dd-80c5-01e928e403eb,
  abstract     = {<p>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 degenerate. 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.</p>},
  author       = {Kikuchi, Tetsuhiro and Morizane, Asuka and Doi, Daisuke and Magotani, Hiroaki and Onoe, Hirotaka and Hayashi, Takuya and Mizuma, Hiroshi and Takara, Sayuki and Takahashi, Ryosuke and Inoue, Haruhisa and Morita, Satoshi and Yamamoto, Michio and Okita, Keisuke and Nakagawa, Masato and Parmar, Malin and Takahashi, Jun},
  issn         = {0028-0836},
  language     = {eng},
  month        = {08},
  number       = {7669},
  pages        = {592--596},
  publisher    = {Nature Publishing Group},
  series       = {Nature},
  title        = {Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model},
  url          = {http://dx.doi.org/10.1038/nature23664},
  volume       = {548},
  year         = {2017},
}