Enhanced cortical neural stem cell identity through short SMAD and WNT 
inhibition in human cerebral organoids facilitates emergence of outer radial 
glial cells

Rosebrock, Daniel; Arora, Sneha; Mutukula, Naresh; Volkman, Rotem; Gralinska, Elzbieta; Balaskas, Anastasios; Aragonés Hernández, Amèlia; Buschow, Rene; Brändl, Björn; Müller, Franz-Josef; Arndt, Peter F.; Vingron, Martin; Elkabetz, Yechiel

doi:10.1038/s41556-022-00929-5

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Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells

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Rosebrock, Daniel
Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Arora, Sneha
Human Brain & Neural Stem Cell Studies (Yechiel Elkabetz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons208940

Mutukula, Naresh
Human Brain & Neural Stem Cell Studies (Yechiel Elkabetz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons228520

Gralinska, Elzbieta
Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons275958

Balaskas, Anastasios
Stem Cell Chromatin (Aydan Bulut-Karslioglu), Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons232021

Aragonés Hernández, Amèlia
Human Brain & Neural Stem Cell Studies (Yechiel Elkabetz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons50118

Buschow, Rene
Microscopy and Cryo-Electron Microscopy (Head: Thorsten Mielke), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons232003

Brändl, Björn
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons220217

Müller, Franz-Josef
Cellular Phenotyping (Franz-Josef Müller), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons50074

Arndt, Peter F.
Evolutionary Genomics (Peter Arndt), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons50613

Vingron, Martin
Transcriptional Regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons208928

Elkabetz, Yechiel
Human Brain & Neural Stem Cell Studies (Yechiel Elkabetz), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Rosebrock, D., Arora, S., Mutukula, N., Volkman, R., Gralinska, E., Balaskas, A., et al. (2022). Enhanced cortical neural stem cell identity through short SMAD and WNT inhibition in human cerebral organoids facilitates emergence of outer radial glial cells. Nature Cell Biology, 24, 981-995. doi:10.1038/s41556-022-00929-5.

Cite as: https://hdl.handle.net/21.11116/0000-000A-B320-7

Abstract

Cerebral organoids exhibit broad regional heterogeneity accompanied by limited cortical cellular diversity despite the tremendous upsurge in derivation methods, suggesting inadequate patterning of early neural stem cells (NSCs). Here we show that a short and early Dual SMAD and WNT inhibition course is necessary and sufficient to establish robust and lasting cortical organoid NSC identity, efficiently suppressing non-cortical NSC fates, while other widely used methods are inconsistent in their cortical NSC-specification capacity. Accordingly, this method selectively enriches for outer radial glia NSCs, which cyto-architecturally demarcate well-defined outer sub-ventricular-like regions propagating from superiorly radially organized, apical cortical rosette NSCs. Finally, this method culminates in the emergence of molecularly distinct deep and upper cortical layer neurons, and reliably uncovers cortex-specific microcephaly defects. Thus, a short SMAD and WNT inhibition is critical for establishing a rich cortical cell repertoire that enables mirroring of fundamental molecular and cyto-architectural features of cortical development and meaningful disease modelling.