孤舟蓑笠翁
(2025-06-29 09:11):
#paper 【doi】10.1038/s41586-025-09151-3;【发表年份】2025年;【期刊】Nature;【标题】Morphodynamics of human early brain organoid development。【内容总结】这项研究想了解人类大脑早期发育过程中细胞外基质(ECM)如何影响脑类器官的形状变化和区域形成。科学家们开发了新技术:1)用荧光标记不同细胞结构(细胞膜、细胞骨架等),2)用光片显微镜长期观察类器官生长,3)计算机分析细胞形状变化。他们发现:1)脑类器官发育分三个阶段(快速生长、腔室融合、成熟),2)添加外源ECM(如Matrigel)能帮助形成更规则的神经上皮结构,3)缺少ECM会导致类器官发育异常,出现更多神经嵴细胞,4)ECM通过WNT和Hippo信号通路影响类器官发育。具体来说,研究团队标记了肌动蛋白、微管等结构,用显微镜追踪数周,发现ECM能促进细胞排列整齐和腔室融合;没有ECM时,YAP1蛋白会上调,激活WNT通路基因WLS,导致类器官尾部化(更像脊髓而不是大脑)。这些发现帮助我们理解ECM在人类大脑发育中的重要作用。
Nature,
2025-6-18.
DOI: 10.1038/s41586-025-09151-3
Morphodynamics of human early brain organoid development
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Abstract:
Abstract Brain organoids enable the mechanistic study of human brain development and provide opportunities to explore self-organization in unconstrained developmental systems1–3. 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 development4. 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 tissue identity. Matrix-induced regional guidance and lumen morphogenesis are linked to the WNT and Hippo (YAP1) signalling pathways, including spatially restricted induction of the WNT ligand secretion mediator (WLS) that marks the earliest emergence of non-telencephalic brain regions. Together, our work provides an inroad into studying human brain morphodynamics and supports a view that matrix-linked mechanosensing dynamics have a central role during brain regionalization.
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