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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)981-995
Number of pages15
JournalNature Cell Biology
Volume24
Issue number6
DOIs
StatePublished - Jun 2022

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