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

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 and Mark Denham ()
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Muyesier Maimaitili: Aarhus University
Muwan Chen: Aarhus University
Fabia Febbraro: Aarhus University
Ekin Ucuncu: Aarhus University
Rachel Kelly: 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
Dragos Niculescu: Aarhus University
Johanne Lauritsen: Aarhus University
Angelo Iannielli: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Ida H. Klæstrup: Aarhus University
Uffe Birk Jensen: Aarhus University
Per Qvist: Aarhus University
Sadegh Nabavi: Aarhus University
Vania Broccoli: Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute
Anders Nykjær: Aarhus University
Marina Romero-Ramos: Aarhus University
Mark Denham: Aarhus University

Nature Communications, 2023, vol. 14, issue 1, 1-23

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.

Date: 2023
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DOI: 10.1038/s41467-023-43471-0

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