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; Mark Denham

doi:10.1038/s41467-023-43471-0

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, Mark Denham

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

3 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	7871
Tidsskrift	Nature Communications
Vol/bind	14
Nummer	1
Antal sider	23
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-023-43471-0
Status	Udgivet - dec. 2023

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10.1038/s41467-023-43471-0Licens: CC BY

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Maimaitili, M., Chen, M., Febbraro, F., Ucuncu, E., Kelly, R., Niclis, J. C., Christiansen, J. R., Mermet-Joret, N., Niculescu, D., Lauritsen, J., Iannielli, A., Klæstrup, I. H., Jensen, U. B., Qvist, P., Nabavi, S., Broccoli, V., Nykjær, A., Romero-Ramos, M., & Denham, M. (2023). Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells. Nature Communications, 14(1), Artikel 7871. https://doi.org/10.1038/s41467-023-43471-0

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title = "Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells",

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.",

author = "Muyesier Maimaitili and Muwan Chen and Fabia Febbraro and Ekin Ucuncu and Rachel Kelly and Niclis, {Jonathan Christos} and Christiansen, {Josefine R{\aa}g{\aa}rd} and No{\"e}mie Mermet-Joret and Dragos Niculescu and Johanne Lauritsen and Angelo Iannielli and Kl{\ae}strup, {Ida H} and Jensen, {Uffe Birk} and Per Qvist and Sadegh Nabavi and Vania Broccoli and Anders Nykj{\ae}r and Marina Romero-Ramos and Mark Denham",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-43471-0",

language = "English",

volume = "14",

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Maimaitili, M , Chen, M , Febbraro, F, Ucuncu, E, Kelly, R, Niclis, JC, Christiansen, JR, Mermet-Joret, N , Niculescu, D , Lauritsen, J, Iannielli, A, Klæstrup, IH , Jensen, UB , Qvist, P , Nabavi, S, Broccoli, V, Nykjær, A , Romero-Ramos, M & Denham, M 2023, 'Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells', Nature Communications, bind 14, nr. 1, 7871. https://doi.org/10.1038/s41467-023-43471-0

TY - JOUR

T1 - Enhanced production of mesencephalic dopaminergic neurons from lineage-restricted human undifferentiated stem cells

AU - Maimaitili, Muyesier

AU - Chen, Muwan

AU - Febbraro, Fabia

AU - Ucuncu, Ekin

AU - Kelly, Rachel

AU - Niclis, Jonathan Christos

AU - Christiansen, Josefine Rågård

AU - Mermet-Joret, Noëmie

AU - Niculescu, Dragos

AU - Lauritsen, Johanne

AU - Iannielli, Angelo

AU - Klæstrup, Ida H

AU - Jensen, Uffe Birk

AU - Qvist, Per

AU - Nabavi, Sadegh

AU - Broccoli, Vania

AU - Nykjær, Anders

AU - Romero-Ramos, Marina

AU - Denham, Mark

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-023-43471-0

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SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 7871

ER -

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

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