Morphodynamics of human early brain organoid development

作者：Akanksha Jain, Gilles Gut, Fátima Sanchís-Calleja, Reto Tschannen, Zhisong He, Nicolas Luginbühl, Fides Zenk, Antonius Chrisnandy, Simon Streib, Christoph Harmel, Ryoko Okamoto, Małgorzata Santel, Makiko Seimiya, René Holtackers, Juliane K. Rohland, Sophie Jansen, Matthias P. Lütolf, J. Gray Camp, Barbara Treutlein · 发表于：Nature · 年份：2025 · DOI：10.1038/s41586-025-09151-3 · 被引用次数：52 · 研究领域：Pluripotent Stem Cells Research、Hippo pathway signaling and YAP/TAZ、Cell Image Analysis Techniques

Abstract Brain organoids enable the mechanistic study of human brain development and provide opportunities to explore self-organization in unconstrained developmental systems 1–3 . Here we establish long-term, live light-sheet microscopy on unguided brain organoids generated from fluorescently labelled human induced pluripotent stem cells, which enables tracking of tissue morphology, cell behaviours and subcellular features over weeks of organoid development 4 . We provide a novel dual-channel, multi-mosaic and multi-protein labelling 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. On the basis of 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 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 ti...