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Robust derivation of transplantable dopamine neurons from human pluripotent stem cells by timed retinoic acid delivery

Author

Listed:
  • Zhanna Alekseenko

    (Karolinska Institutet)

  • José M. Dias

    (Karolinska Institutet)

  • Andrew F. Adler

    (Lund University
    Lund University)

  • Mariya Kozhevnikova

    (Karolinska Institutet)

  • Josina Anna Lunteren

    (Karolinska Institutet)

  • Sara Nolbrant

    (Lund University
    Lund University)

  • Ashwini Jeggari

    (Karolinska Institutet)

  • Svitlana Vasylovska

    (Karolinska Institutet)

  • Takashi Yoshitake

    (Karolinska Institutet)

  • Jan Kehr

    (Karolinska Institutet
    Pronexus Analytical AB)

  • Marie Carlén

    (Karolinska Institutet
    Karolinska Institutet)

  • Andrey Alexeyenko

    (Karolinska Institutet
    Science for Life Laboratory)

  • Malin Parmar

    (Lund University
    Lund University)

  • Johan Ericson

    (Karolinska Institutet)

Abstract

Stem cell therapies for Parkinson’s disease (PD) have entered first-in-human clinical trials using a set of technically related methods to produce mesencephalic dopamine (mDA) neurons from human pluripotent stem cells (hPSCs). Here, we outline an approach for high-yield derivation of mDA neurons that principally differs from alternative technologies by utilizing retinoic acid (RA) signaling, instead of WNT and FGF8 signaling, to specify mesencephalic fate. Unlike most morphogen signals, where precise concentration determines cell fate, it is the duration of RA exposure that is the key-parameter for mesencephalic specification. This concentration-insensitive patterning approach provides robustness and reduces the need for protocol-adjustments between hPSC-lines. RA-specified progenitors promptly differentiate into functional mDA neurons in vitro, and successfully engraft and relieve motor deficits after transplantation in a rat PD model. Our study provides a potential alternative route for cell therapy and disease modelling that due to its robustness could be particularly expedient when use of autologous- or immunologically matched cells is considered.

Suggested Citation

  • Zhanna Alekseenko & José M. Dias & Andrew F. Adler & Mariya Kozhevnikova & Josina Anna Lunteren & Sara Nolbrant & Ashwini Jeggari & Svitlana Vasylovska & Takashi Yoshitake & Jan Kehr & Marie Carlén & , 2022. "Robust derivation of transplantable dopamine neurons from human pluripotent stem cells by timed retinoic acid delivery," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30777-8
    DOI: 10.1038/s41467-022-30777-8
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    References listed on IDEAS

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    1. Daisuke Doi & Hiroaki Magotani & Tetsuhiro Kikuchi & Megumi Ikeda & Satoe Hiramatsu & Kenji Yoshida & Naoki Amano & Masaki Nomura & Masafumi Umekage & Asuka Morizane & Jun Takahashi, 2020. "Pre-clinical study of induced pluripotent stem cell-derived dopaminergic progenitor cells for Parkinson’s disease," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    2. Sonja Kriks & Jae-Won Shim & Jinghua Piao & Yosif M. Ganat & Dustin R. Wakeman & Zhong Xie & Luis Carrillo-Reid & Gordon Auyeung & Chris Antonacci & Amanda Buch & Lichuan Yang & M. Flint Beal & D. Jam, 2011. "Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease," Nature, Nature, vol. 480(7378), pages 547-551, December.
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    Cited by:

    1. Muyesier Maimaitili & Muwan Chen & Fabia Febbraro & Ekin Ucuncu & Rachel Kelly & Jonathan Christos Niclis & Josefine Rågård Christiansen & Noëmie Mermet-Joret & Dragos Niculescu & Johanne Lauritsen & , 2023. "Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells," Nature Communications, Nature, vol. 14(1), pages 1-23, December.

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