Human Brain Organoids on a Chip Reveal the Physics of Folding

Nature Physics
Eyal KarzbrunOrly Reiner

Abstract

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 micro-fabricated 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 in vivo, it models the physics of the folding brain remarkably well. Our on-...Continue Reading

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Methods Mentioned

BETA
Fluorescence
irradiate
AFM
atomic force microscopy
fluorescence-activated cell sorting
transfection
FACS
fluorescence imaging
RNA-seq

Software Mentioned

FastQC
R
STAR
dendsort
hclust
Cutadapt
GeneAnalytics
TapeStation
Matlab
FIJI

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