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PreprintCited by 73Neurogenesis and neuroplasticity mechanismsDevelopmental Biology and Gene RegulationPluripotent Stem Cells Research

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Morphodynamics of human early brain organoid development

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Jain, Akanksha, Gut, Gilles, Sanchis-Calleja, Fátima, Okamoto, Ryoko, Streib, Simon, He, Zhisong, Zenk, Fides, Santel, Malgorzata, Seimiya, Makiko, Holtackers, René, Jansen, Sophie Martina Johanna, Camp, J. Gray, Treutlein, Barbara·2023·Nature
DOI 10.1101/2023.08.21.553827PMC PMC12390842

Preprint — published as 10.1038/s41586-025-09151-3 · Paper page

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Abstract

Brain organoids enable the mechanistic study of human brain development, and provide opportunities to explore self-organization in unconstrained developmental systems. Here, we establish long-term, live light sheet microscopy on unguided brain organoids generated from fluorescently labeled human induced pluripotent stem cells, which enables tracking of tissue morphology, cell behaviors, and subcellular features over weeks of organoid development. We provide a novel dual-channel, multi-mosaic and multi-protein labeling strategy combined with a computational demultiplexing approach to enable simultaneous quantification of distinct subcellular features during organoid development. We track Actin, Tubulin, plasma membrane, nucleus, and nuclear envelope dynamics, and quantify cell morphometric and alignment changes during tissue state transitions including neuroepithelial induction, maturation, lumenization, and brain regionalization. Based on imaging and single-cell transcriptome modalities, we find that lumenal expansion and cell morphotype composition within the developing neuroepithelium are associated with modulation of gene expression programs involving extracellular matrix (ECM) pathway regulators and mechanosensing. We show that an extrinsically provided matrix enhances lumen expansion as well as telencephalon formation, and unguided organoids grown in the absence of an extrinsic matrix have altered morphologies with increased neural crest and caudalized tissue identity. Matrixinduced regional guidance and lumen morphogenesis are linked to the WNT and Hippo (YAP1) signaling pathways, including spatially restricted induction of the Wnt Ligand Secretion Mediator (WLS) that marks the earliest emergence of nontelencephalic brain regions. Altogether, our work provides a new inroad into studying human brain morphodynamics, and supports a view that matrix-linked mechanosensing dynamics play a central role during brain regionalization.

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Metadata

Authors
Jain, A., Gut, G., Sanchis-Calleja, F., Okamoto, R., Streib, S., He, Z., Zenk, F., Santel, M., Seimiya, M., Holtackers, R., Jansen, S. M. J., Camp, J. G., & Treutlein, B.
Affiliations
  • ETH Zurich (CH)
  • F. Hoffmann-La Roche AG (CH)
Corresponding author
  • Jain, Akanksha
  • Treutlein, Barbara
ORCID
Venue
Nature
Publisher
openRxiv
Published
2023-08-22
Volume
644
Issue
8078
Pages
1010-1019
ISSN
0028-0836 (ISSN-L)
DOI
10.1101/2023.08.21.553827
PMC
PMC12390842
OpenAlex
W4411413694
Cited by
73
References
1
Citations by year
2026: 33 · 2025: 31 · 2024: 7 · 2023: 2
FWCI
23.82
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
Funders
  • National Science Foundation
  • Silicon Valley Community Foundation
  • Children’s Hospital of Wisconsin Research Institute
  • Murdoch Children's Research Institute
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (192604, 310030)
  • Murdoch University
  • Eidgenössische Technische Hochschule Zürich
  • National Center of Competence in Research Chemical Biology
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Keywords
brain organoids, human brain development, morphodynamics, induced pluripotent stem cells, light-sheet microscopy, neuroepithelium, brain regionalization, extracellular matrix, mechanosensing, Wnt signaling, Hippo signaling pathway, YAP, neural crest, cell morphometry, cell alignment
MeSH terms
YAP-Signaling Proteins, Brain, Extracellular Matrix, Humans, Morphogenesis, Neural Crest, Organoids, Telencephalon, Adaptor Proteins, Signal Transducing, Induced Pluripotent Stem Cells, Single-Cell Analysis

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