Human neural tube morphogenesis in vitro by geometric constraints

Karzbrun Eyal; Khankhel Aimal H.; Megale Heitor C.; Glasauer Stella M. K.; Wyle Yofiel; Britton George; Warmflash Aryeh; Kosik Kenneth S.; Siggia Eric D.; Shraiman Boris I; Streichan Sebastian J.

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Human neural tube morphogenesis in vitro by geometric constraints

机译：人体神经管由几何限制体内的形态发生

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Understanding human organ formation is a scientific challenge with far-reaching medical implications(1,2). Three-dimensional stem-cell cultures have provided insights into human cell differentiation(3,4). However, current approaches use scaffold-free stem-cell aggregates, which develop non-reproducible tissue shapes and variable cell-fate patterns. This limits their capacity to recapitulate organ formation. Here we present a chip-based culture system that enables self-organization of micropatterned stem cells into precise three-dimensional cell-fate patterns and organ shapes. We use this system to recreate neural tube folding from human stem cells in a dish. Upon neural induction(5,6), neural ectoderm folds into a millimetre-long neural tube covered with non-neural ectoderm. Folding occurs at 90% fidelity, and anatomically resembles the developing human neural tube. We find that neural and non-neural ectoderm are necessary and sufficient for folding morphogenesis. We identify two mechanisms drive folding: (1) apical contraction of neural ectoderm, and (2) basal adhesion mediated via extracellular matrix synthesis by non-neural ectoderm. Targeting these two mechanisms using drugs leads to morphological defects similar to neural tube defects. Finally, we show that neural tissue width determines neural tube shape, suggesting that morphology along the anterior-posterior axis depends on neural ectoderm geometry in addition to molecular gradients(7). Our approach provides a new route to the study of human organ morphogenesis in health and disease.

机译：了解人体组织形成是一种科学挑战，具有深远的医学影响（1,2）。三维干细胞培养物为人细胞分化（3,4）提供了见解。然而，目前的方法使用无支腿的干细胞聚集体，其开发不可重复的组织形状和可变的细胞命运模式。这限制了它们的综合体形成的能力。在这里，我们提出了一种基于芯片的培养系统，使得微型解放干细胞的自组织能够精确三维细胞 - 命运模式和器官形状。我们使用该系统在盘中的人干细胞中重建神经管。在神经诱导（5,6）时，神经外胚层折叠成覆盖着非神经外胚层的毫米长的神经管。折叠发生在90％的保险费中，并对显影的人类神经管进行解剖学。我们发现神经和非神经外胚层是必要的，并且足以用于折叠形态发生。我们鉴定了两种机制驱动折叠：（1）神经外胚层的顶端收缩，（2）通过非神经外胚层的细胞外基质合成介导的基底粘附。使用药物靶向这两种机制导致类似于神经管缺陷的形态缺陷。最后，我们表明神经组织宽度决定了神经管形状，表明除了分子梯度（7）之外，沿前后轴线的形态取决于神经外胚层几何形状。我们的方法为健康和疾病中的人体器官形态发生研究提供了新的途径。

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《Nature》 |2021年第7884期|268-272|共5页
作者
Karzbrun Eyal; Khankhel Aimal H.; Megale Heitor C.; Glasauer Stella M. K.; Wyle Yofiel; Britton George; Warmflash Aryeh; Kosik Kenneth S.; Siggia Eric D.; Shraiman Boris I; Streichan Sebastian J.;
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作者单位

Univ Calif Santa Barbara Dept Phys Santa Barbara CA 93106 USA|Kavli Inst Theoret Phys Santa Barbara CA 93106 USA;

Univ Calif Santa Barbara Biomol Sci & Engn Santa Barbara CA 93106 USA;

Univ Calif Santa Barbara Dept Phys Santa Barbara CA 93106 USA;

Univ Calif Santa Barbara Dept Mol Dev Biol Cellular Santa Barbara CA 93106 USA|Univ Calif Santa Barbara Neurosci Res Inst Santa Barbara CA 93106 USA;

Univ Calif Santa Barbara Dept Mol Dev Biol Cellular Santa Barbara CA 93106 USA;

Rice Univ Syst Synthet & Phys Biol Program Houston TX USA;

Rice Univ Dept Biosci Houston TX USA|Rice Univ Dept Bioengn Houston TX USA;

Univ Calif Santa Barbara Dept Mol Dev Biol Cellular Santa Barbara CA 93106 USA|Univ Calif Santa Barbara Neurosci Res Inst Santa Barbara CA 93106 USA;

Rockefeller Univ Ctr Studies Phys & Biol 1230 York Ave New York NY 10021 USA;

Univ Calif Santa Barbara Dept Phys Santa Barbara CA 93106 USA|Kavli Inst Theoret Phys Santa Barbara CA 93106 USA;

Univ Calif Santa Barbara Dept Phys Santa Barbara CA 93106 USA|Univ Calif Santa Barbara Biomol Sci & Engn Santa Barbara CA 93106 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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专利

1. The interaction between Shroom3 and Rho-kinase is required for neural tube morphogenesis in mice The interaction between Shroom3 and Rho-kinase is required for neural tube morphogenesis in mice The interaction between Shroom3 and Rho-kinase is required for neural tube morphogenesis in mice [J] . Jenna K. Zalewski, Debamitra Das, Swarna Mohan, Biology Open . 2014,第9期

机译：小鼠神经管形态发生需要Shroom3和Rho激酶之间的相互作用小鼠神经管形态发生需要Shroom3和Rho激酶之间的相互作用小鼠神经管形态发生需要Shroom3和Rho激酶之间的相互作用
2. Human neural organoid model exhibiting early neural tube morphogenesis [J] . Ju-Hyun Lee, Mohammed R. Shaker, Hyun Jung Kim, IBRO Reports . 2019,第2期

机译：展示早期神经管形态发生的人类神经类器官模型
3. Neural tube closure in humans initiates at multiple sites: evidence from human embryos and implications for the pathogenesis of neural tube defects. [J] . Nakatsu T, Uwabe C, Shiota K Anatomy and embryology . 2000,第6期

机译：人体中的神经管闭合在多个部位开始：来自人类胚胎的证据以及对神经管缺陷的发病机制的影响。
4. Neural tube morphogenesis in synthetic 3D microenvironments [C] . Adrian Ranga, Mehmet Girgin, Elly M Tanaka, World biomaterials congress . 2016

机译：合成3D微环境中的神经管形态发生
5. Requirements for Wnt signaling in morphogenesis of the neural crest, neural tube, and craniofacial skeleton of zebrafish embryos. [D] . Piloto, Sarah. 2010

机译：斑马鱼胚胎神经c，神经管和颅面骨架形态发生中Wnt信号的要求。
6. Migration and differentiation of neural crest and ventral neural tube cells in vitro: implications for in vitro and in vivo studies of the neural crest [O] . JF Loring, DL Barker, CA Erickson 1988

机译：神经c和腹侧神经管细胞的体外迁移和分化：对神经rest的体外和体内研究的意义
7. Neural tube closure in humans initiates at multiple sites: evidence from human embryos and implications for the pathogenesis of neural tube defects [O] . Tomoko Nakatsu, Chigako Uwabe, K. Shiota 2000

机译：人类的神经管闭合在多个地点发起：来自人类胚胎的证据和针对神经管缺陷发病机制的影响

Human neural tube morphogenesis in vitro by geometric constraints

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