BMP, MEK, and WNT inhibition with NGN2 expression for rapid generation of hiPSC-derived neurons amenable to regional patterning

Human induced pluripotent stem cells (hiPSCs) are a promising tool for studying neurological diseases and developing therapies for neurodegenerative diseases. Differentiation of hiPSCs into neurons can be achieved by dual SMAD inhibition (dSMADi) or by induced neurogenin 2 (NGN2) overexpression ("iNGN2"). Starting directly from hiPSCs, iNGN2 shortens the time to a neuronal stage but leads to neurons partially resembling peripheral or posterior fates while dSMADi more faithfully recapitulates telencephalic development. To modify the iNGN2 approach, we applied an accelerated induction paradigm that is dependent on the inhibition of BMP, MEK, and WNT pathways ("BMWi"), to commit hiPSCs into a telencephalic fate before iNGN2. The resulting neurons showed strong expression of telencephalic markers, with decreased levels of peripheral and posterior marker genes compared to iNGN2 alone. The resulting telencephalic neurons are suitable for a tau aggregation assay. Furthermore, we could demonstrate that during BMWi treatment, the cells are amenable to additional regional patterning cues. This allowed the generation of neurons from different regions of the CNS and peripheral nervous system (PNS), which will significantly facilitate in vitro modeling of a range of neurodevelopmental and neurodegenerative disorders.

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Publication Details

Journal
Stem Cell Reports
Published
2025-06-19
DOI
https://doi.org/10.1016/j.stemcr.2025.102539
Citations
2
Primary Topic
Pluripotent Stem Cells Research
Type
article
Field-Weighted Citation Impact
1.61
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BMP, MEK, and WNT inhibition with NGN2 expression for rapid generation of hiPSC-derived neurons amenable to regional patterning

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article

BMP, MEK, and WNT inhibition with NGN2 expression for rapid generation of hiPSC-derived neurons amenable to regional patterning

Justine D. Manos, Jürgen Korffmann, Christopher Untucht, Michael Wolf, Nathalie Nicolaisen, Melanie S. Brennan, Markus P. Kummer, Christopher Sliwinski, Daniela Geist, Loan Miller, Benjamin Mielich‐Süss, Tanja Lange, Ian W. Weidling, Ruven Wilkens, Miroslav Cik, Astrid Wachter, Michaela J. Heimann, Lamiaa Bahnassawy, David C. Schöndorf, Lydia Reinhardt, Heyne Lee, Veronika Heil, Rüdiger Rudolf, Alexandra Kowalski, Christiane Habich, Julian Röwe, Peter Reinhardt, Mathias Hafner
article en
2 citations

Abstract

Human induced pluripotent stem cells (hiPSCs) are a promising tool for studying neurological diseases and developing therapies for neurodegenerative diseases. Differentiation of hiPSCs into neurons can be achieved by dual SMAD inhibition (dSMADi) or by induced neurogenin 2 (NGN2) overexpression ("iNGN2"). Starting directly from hiPSCs, iNGN2 shortens the time to a neuronal stage but leads to neurons partially resembling peripheral or posterior fates while dSMADi more faithfully recapitulates telencephalic development. To modify the iNGN2 approach, we applied an accelerated induction paradigm that is dependent on the inhibition of BMP, MEK, and WNT pathways ("BMWi"), to commit hiPSCs into a telencephalic fate before iNGN2. The resulting neurons showed strong expression of telencephalic markers, with decreased levels of peripheral and posterior marker genes compared to iNGN2 alone. The resulting telencephalic neurons are suitable for a tau aggregation assay. Furthermore, we could demonstrate that during BMWi treatment, the cells are amenable to additional regional patterning cues. This allowed the generation of neurons from different regions of the CNS and peripheral nervous system (PNS), which will significantly facilitate in vitro modeling of a range of neurodevelopmental and neurodegenerative disorders.

Stem Cell ReportsVol. 20(7)
Technische Hochschule Mannheim (DE), Lake County (US), AbbVie (United States) (US), AbbVie (Germany) (DE), Klinikum Ludwigshafen (DE)
Zero hunger
Openalex Percentile: Top 16%
Pluripotent Stem Cells Research
1.61
DOIOpen Access PDFOpenAlex
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