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

Autor: Maimaitili M; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark., Chen M; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark., Febbraro F; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Clinical Genetics, Aarhus University Hospital, 8200, Aarhus, Denmark., Ucuncu E; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark., Kelly R; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark., Niclis JC; Cell Therapy Discovery, Cell Therapy R&D, Novo Nordisk, Måløv, Denmark., Christiansen JR; Cell Therapy Discovery, Cell Therapy R&D, Novo Nordisk, Måløv, Denmark., Mermet-Joret N; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Molecular Biology and Genetics, Aarhus University, 8000C, Aarhus, Denmark.; Center of Excellence PROMEMO, Aarhus University, Aarhus, Denmark., Niculescu D; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark.; Center of Excellence PROMEMO, Aarhus University, Aarhus, Denmark., Lauritsen J; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark., Iannielli A; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.; CNR Institute of Neuroscience, 20129, Milan, Italy., Klæstrup IH; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark., Jensen UB; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Clinical Genetics, Aarhus University Hospital, 8200, Aarhus, Denmark., Qvist P; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark.; Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, 8000C, Aarhus, Denmark.; Centre for Integrative Sequencing, iSEQ, Aarhus University, 8000C, Aarhus, Denmark.; Centre for Genomics and Personalized Medicine, CGPM, Aarhus University, 8000C, Aarhus, Denmark., Nabavi S; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Molecular Biology and Genetics, Aarhus University, 8000C, Aarhus, Denmark.; Center of Excellence PROMEMO, Aarhus University, Aarhus, Denmark., Broccoli V; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy.; CNR Institute of Neuroscience, 20129, Milan, Italy., Nykjær A; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark.; Center of Excellence PROMEMO, Aarhus University, Aarhus, Denmark., Romero-Ramos M; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark.; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark., Denham M; Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic EMBL Partnership for Molecular Medicine, Aarhus University, 8000C, Aarhus, Denmark. mden@dandrite.au.dk.; Department of Biomedicine, Aarhus University, 8000C, Aarhus, Denmark. mden@dandrite.au.dk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Dec 05; Vol. 14 (1), pp. 7871. Date of Electronic Publication: 2023 Dec 05.
DOI: 10.1038/s41467-023-43471-0
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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