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- Title
Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells.
- Authors
Maimaitili, Muyesier; Chen, Muwan; Febbraro, Fabia; Ucuncu, Ekin; Kelly, Rachel; Niclis, Jonathan Christos; Christiansen, Josefine Rågård; Mermet-Joret, Noëmie; Niculescu, Dragos; Lauritsen, Johanne; Iannielli, Angelo; Klæstrup, Ida H.; Jensen, Uffe Birk; Qvist, Per; Nabavi, Sadegh; Broccoli, Vania; Nykjær, Anders; Romero-Ramos, Marina; Denham, Mark
- 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.The differentiation of human pluripotent stem cells into dopaminergic neurons is challenging. Here, the authors developed lineage-restricted undifferentiated stem cells, which have an enhanced ability for differentiating into dopaminergic neurons.
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-43471-0