期刊
NATURE PHYSICS
卷 14, 期 5, 页码 515-+出版社
NATURE RESEARCH
DOI: 10.1038/s41567-018-0046-7
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资金
- Legacy Heritage Biomedical Program of the Israel Science Foundation [2041/16]
- ERA-NET Neuron [3-0000-12276]
- European Cooperation on Science and Technology (COST Action) [CA16118]
- Nella and Leon Benoziyo Center for Neurological Diseases
- Jeanne and Joseph Nissim Foundation for Life Sciences Research
- Wohl Biology Endowment Fund
- Lulu P. AMP
- David J. Levidow Fund for Alzheimers Diseases and Neuroscience Research
- Helen and Martin Kimmel Stem Cell Research Institute
- Kekst Family Institute for Medical Genetics
- David and Fela Shapell Family Center for Genetic Disorders Research
- European Research Council (ERC-CoG CellNaivety)
- Flight Attendant Medical Research Council (FAMRI)
- Israel Science Foundation Morasha Program
Human brain wrinkling has been implicated in neurodevelopmental disorders and yet its origins remain unknown. Polymer gel models suggest that wrinkling emerges spontaneously due to compression forces arising during differential swelling, but these ideas have not been tested in a living system. Here, we report the appearance of surface wrinkles during the in vitro development and self-organization of human brain organoids in a microfabricated compartment that supports in situ imaging over a timescale of weeks. We observe the emergence of convolutions at a critical cell density and maximal nuclear strain, which are indicative of a mechanical instability. We identify two opposing forces contributing to differential growth: cytoskeletal contraction at the organoid core and cell-cycle-dependent nuclear expansion at the organoid perimeter. The wrinkling wavelength exhibits linear scaling with tissue thickness, consistent with balanced bending and stretching energies. Lissencephalic (smooth brain) organoids display reduced convolutions, modified scaling and a reduced elastic modulus. Although the mechanism here does not include the neuronal migration seen in vivo, it models the physics of the folding brain remarkably well. Our on-chip approach offers a means for studying the emergent properties of organoid development, with implications for the embryonic human brain.
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