Sliced Human Cortical Organoids for Modeling Distinct Cortical Layer Formation
Open accessAbstract
Human brain organoids provide unique platforms for modeling development and diseases by recapitulating the architecture of the embryonic brain. However, current organoid methods are limited by interior hypoxia and cell death due to insufficient surface diffusion, preventing generation of architecture resembling late developmental stages. Here, we report the sliced neocortical organoid (SNO) system, which bypasses the diffusion limit to prevent cell death over long-term cultures. This method leads to sustained neurogenesis and formation of an expanded cortical plate that establishes distinct upper and deep cortical layers for neurons and astrocytes, resembling the third trimester embryonic human neocortex. Using the SNO system, we further identify a critical role of WNT/β-catenin signaling in regulating human cortical neuron subtype fate specification, which is disrupted by a psychiatric-disorder-associated genetic mutation in patient induced pluripotent stem cell (iPSC)-derived SNOs. These results demonstrate the utility of SNOs for investigating previously inaccessible human-specific, late-stage cortical development and disease-relevant mechanisms.
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A recent study reported a slicing culture method for neocortical organoid generation that sectioned organoids into 500-μm-thick slices to overcome interior hypoxia and cell death over long-term cultures.
“A recent study reported a slicing culture method for neocortical organoid generation that sectioned the organoids into 500-μm-thick slices to overcome interior hypoxia and cell death over long-term cultures [39].”
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“Although other approaches, such as organoid vascularization ( 69 ) or slicing ( 70 ), have been applied to reduce organoid hypoxia and necrosis, our platform does not require introducing vascular cells or continued handling of individual organoids, and thus provides an easy- to-use system for…”
- Authors
- Qian, X., Su, Y., Adam, C. D., Deutschmann, A. U., Pather, S. R., Goldberg, E. M., Su, K., Li, S., Lu, L., Jacob, F., Nguyen, P. T. T., Huh, S., Hoke, A., Swinford-Jackson, S. E., Wen, Z., Gu, X., Pierce, R. C., Wu, H., Briand, L. A., Chen, H. I., Wolf, J. A., Song, H., & Ming, G.-L.
- Affiliations
- Johns Hopkins University (US)
- University of Pennsylvania (US)
- Children's Hospital of Philadelphia (US)
- Emory University (US)
- Nantong University (CN)
- Temple University (US)
- Philadelphia VA Medical Center (US)
- Corresponding author
- Ming, Guo-li
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2020-05
- Volume
- 26
- Issue
- 5
- Pages
- 766-781.e9
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC7366517
- OpenAlex
- W3009673357
- Cited by
- 479
- References
- 20
- Citations by year
- 2026: 59 · 2025: 83 · 2024: 92 · 2023: 81 · 2022: 84 · 2021: 55 · 2020: 24 · 2018: 1
- FWCI
- 24.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- National Institutes of Health
- 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
- human brain organoids, cortical layer formation, cortical development, hypoxia, surface diffusion, neurogenesis, cortical plate, astrocytes, Wnt/β-catenin signaling, neuronal subtype specification, iPSC-derived neurons, mental illness
- MeSH terms
- Humans, Neurons, Organoids, Neocortex, Neurogenesis, Induced Pluripotent Stem Cells
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