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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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.
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Guided cortical organoid differentiation yields highly reproducible organoids compared with unguided organoid differentiation.
“Furthermore, several studies have shown that guided cortical organoid differentiation yields highly reproducible organoids as compared to unguided organoid differentiation (72–74).”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [72]
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FGF8-mediated gene regulation affects regional identity in human cerebral organoids
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Manufacturing Uniform Cerebral Organoids for Neurological Disease Modeling and Drug Evaluation
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“Furthermore, several studies have shown that guided cortical organoid differentiation yields highly reproducible organoids as compared to unguided organoid differentiation ( 72 – 74 ).”
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Age-Related Neurodegenerative Diseases: A Stem Cell’s Perspective
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Asteroid impact: the potential of astrocytes to modulate human neural networks within organoids
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CAbiNet: joint clustering and visualization of cells and genes for single-cell transcriptomics
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Modeling forebrain regional development and connectivity by human brain organoids
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Progression of differentiation of iPSCs into specific subtypes of neurons
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Advances in three-dimensional modeling of ischemic injury
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Organoids in COVID-19: can we break the glass ceiling?
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Human Brain Organoids in the Preclinical Phase of Drug Development for Migraine
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miR-151-5p regulates neural stem cell fate by targeting APH1A to modulate Notch signaling gradients
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Rapid and Robust Generation of Human Cortical Interneurons from Induced Neural Stem Cells
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Emerging Regenerative Medicine for Spinal Cord Injury: Spinal Cord Organoids-on-a-Chip
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CLASSIFYING OF TEACHING-LEARNING RESULTS FROM UNIVERSITY STUDENTS SURVEYS
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Not all cortical organoids are created equal
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Self-citationIt takes two to expand the cortex
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- Authors
- Rosebrock, D., Arora, S., Mutukula, N., Volkman, R., Gralinska, E., Balaskas, A., Aragonés Hernández, A., Buschow, R., Brändl, B., Müller, F.-J., Arndt, P. F., Vingron, M., & Elkabetz, Y.
- Affiliations
- Max Planck Institute for Molecular Genetics (DE)
- Tel Aviv University (IL)
- Corresponding author
- Elkabetz, Yechiel
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2022-06
- Volume
- 24
- Issue
- 6
- Pages
- 981-995
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC9203281
- OpenAlex
- W4282570172
- Cited by
- 89
- References
- 71
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 23 · 2023: 20 · 2022: 3 · 2021: 1
- FWCI
- 6.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature Cell Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
- Refubium (Universitätsbibliothek der Freien Universität Berlin) (submittedVersion, cc-by)
- Universitätsbibliothek der FU Berlin Hochschulschriftenstelle u. Dokumentenserver (cc-by)
- Funders
- Max-Planck-Gesellschaft
- Israel Science Foundation (1592/13, 1939/15)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- brain organoids, SMAD inhibition, Wnt signaling inhibition, outer radial glia, cortical development, microcephaly, disease modeling
- MeSH terms
- Cell Differentiation, Cerebral Cortex, Humans, Neurons, Organoids, Neurogenesis, Neural Stem Cells, Ependymoglial Cells
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