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Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells

Author

Listed:
  • Muyesier Maimaitili

    (Aarhus University
    Aarhus University)

  • Muwan Chen

    (Aarhus University
    Aarhus University)

  • Fabia Febbraro

    (Aarhus University
    Aarhus University Hospital)

  • Ekin Ucuncu

    (Aarhus University
    Aarhus University)

  • Rachel Kelly

    (Aarhus University
    Aarhus University)

  • Jonathan Christos Niclis

    (Cell Therapy Discovery, Cell Therapy R&D, Novo Nordisk)

  • Josefine Rågård Christiansen

    (Cell Therapy Discovery, Cell Therapy R&D, Novo Nordisk)

  • Noëmie Mermet-Joret

    (Aarhus University
    Aarhus University
    Aarhus University)

  • Dragos Niculescu

    (Aarhus University
    Aarhus University
    Aarhus University)

  • Johanne Lauritsen

    (Aarhus University
    Aarhus University)

  • Angelo Iannielli

    (Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
    CNR Institute of Neuroscience)

  • Ida H. Klæstrup

    (Aarhus University
    Aarhus University)

  • Uffe Birk Jensen

    (Aarhus University
    Aarhus University Hospital)

  • Per Qvist

    (Aarhus University
    Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH
    Aarhus University
    Aarhus University)

  • Sadegh Nabavi

    (Aarhus University
    Aarhus University
    Aarhus University)

  • Vania Broccoli

    (Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
    CNR Institute of Neuroscience)

  • Anders Nykjær

    (Aarhus University
    Aarhus University
    Aarhus University)

  • Marina Romero-Ramos

    (Aarhus University
    Aarhus University)

  • Mark Denham

    (Aarhus University
    Aarhus University)

Abstract

Current differentiation protocols for generating mesencephalic dopaminergic (mesDA) neurons from human pluripotent stem cells result in grafts containing only a small proportion of mesDA neurons when transplanted in vivo. In this study, we develop lineage-restricted undifferentiated stem cells (LR-USCs) from pluripotent stem cells, which enhances their potential for differentiating into caudal midbrain floor plate progenitors and mesDA neurons. Using a ventral midbrain protocol, 69% of LR-USCs become bona fide caudal midbrain floor plate progenitors, compared to only 25% of human embryonic stem cells (hESCs). Importantly, LR-USCs generate significantly more mesDA neurons under midbrain and hindbrain conditions in vitro and in vivo. We demonstrate that midbrain-patterned LR-USC progenitors transplanted into 6-hydroxydopamine-lesioned rats restore function in a clinically relevant non-pharmacological behavioral test, whereas midbrain-patterned hESC-derived progenitors do not. This strategy demonstrates how lineage restriction can prevent the development of undesirable lineages and enhance the conditions necessary for mesDA neuron generation.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43471-0
    DOI: 10.1038/s41467-023-43471-0
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    1. Trygve E. Bakken & Nikolas L. Jorstad & Qiwen Hu & Blue B. Lake & Wei Tian & Brian E. Kalmbach & Megan Crow & Rebecca D. Hodge & Fenna M. Krienen & Staci A. Sorensen & Jeroen Eggermont & Zizhen Yao & , 2021. "Comparative cellular analysis of motor cortex in human, marmoset and mouse," Nature, Nature, vol. 598(7879), pages 111-119, October.
    2. Vania Broccoli & Edoardo Boncinelli & Wolfgang Wurst, 1999. "The caudal limit of Otx2 expression positions the isthmic organizer," Nature, Nature, vol. 401(6749), pages 164-168, September.
    3. 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.
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