학술논문
Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells
Document Type
article
Author
Muyesier Maimaitili; Muwan Chen; Fabia Febbraro; Ekin Ucuncu; Rachel Kelly; Jonathan Christos Niclis; Josefine Rågård Christiansen; 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
Source
Nature Communications, Vol 14, Iss 1, Pp 1-23 (2023)
Subject
Language
English
ISSN
2041-1723
Abstract
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.