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

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  • Muyesier Maimaitili
  • Muwan Chen
  • Fabia Febbraro
  • Ekin Ucuncu
  • Rachel Kelly
  • Jonathan Christos Niclis
  • Christiansen, Josefine Rågård
  • Noëmie Mermet-Joret
  • Dragos Niculescu
  • Johanne Lauritsen
  • Angelo Iannielli
  • Ida H Klæstrup
  • Uffe Birk Jensen
  • Per Qvist
  • Sadegh Nabavi
  • Vania Broccoli
  • Anders Nykjær
  • Marina Romero-Ramos
  • Mark Denham

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.

Original languageEnglish
Article number7871
JournalNature Communications
Volume14
Number of pages23
ISSN2041-1723
DOIs
Publication statusPublished - 2023
Externally publishedYes

Bibliographical note

© 2023. The Author(s).

    Research areas

  • Humans, Rats, Animals, Dopaminergic Neurons/metabolism, Transcription Factors/metabolism, Cell Differentiation/physiology, Mesencephalon, Pluripotent Stem Cells/metabolism

ID: 390196047