Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells
Research output: Contribution to journal › Journal article › Research › peer-review
Documents
- Fulltext
Final published version, 5.99 MB, PDF document
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 language | English |
---|---|
Article number | 7871 |
Journal | Nature Communications |
Volume | 14 |
Number of pages | 23 |
ISSN | 2041-1723 |
DOIs | |
Publication status | Published - 2023 |
Externally published | Yes |
Bibliographical note
© 2023. The Author(s).
- Humans, Rats, Animals, Dopaminergic Neurons/metabolism, Transcription Factors/metabolism, Cell Differentiation/physiology, Mesencephalon, Pluripotent Stem Cells/metabolism
Research areas
ID: 390196047