Hydraulic control of mammalian embryo size and cell fate
Hydraulic control of mammalian embryo size and cell fate
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DOI：
10.1038/s41586-019-1309-x
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发表时间：
2019-07-04
期刊：
影响因子：
64.8
通讯作者：
Hiiragi, Takashi
中科院分区：
文献类型：
--
作者：
Chan, Chii Jou;Costanzo, Maria;Hiiragi, Takashi
大小控制是组织发育和体内平衡的基础（1,2）。尽管细胞增殖在这些过程中的作用已被广泛研究，但控制胚胎大小的机制以及这些机制如何影响细胞命运仍然未知。本研究以小鼠囊胚为模型，揭示充液腔在控制胚胎大小和细胞命运规范中的关键作用。我们发现，在囊胚发育过程中，管腔压力增加了两倍，这转化为伴随的细胞皮质张力和管腔排列的滋养外胚层组织硬度的增加。皮质张力的增加导致血管蛋白机械感应和功能紧密连接的成熟，这建立了一个积极的反馈回路，以适应管腔的生长。当皮层张力达到临界阈值时，细胞-细胞粘附在有丝分裂进入时不能维持，从而导致滋养外胚层破裂和囊胚塌陷。一个简单的水力门控振荡理论概括了观察到的大小振荡动力学，并预测了胚胎大小随组织体积的缩放。该理论进一步预测，紧密连接被破坏或组织刚度增加导致胚胎尺寸变小，我们通过生物物理、胚胎学、药理学和遗传扰动验证了这一点。管腔压力和大小的变化可以影响滋养外胚层的细胞分裂模式，从而影响细胞的分配和命运。我们的研究揭示了管腔压力和组织力学如何在组织尺度上控制胚胎的大小，这与细胞在细胞尺度上的位置和命运是耦合的。
Size control is fundamental in tissue development and homeostasis(1,2). Although the role of cell proliferation in these processes has been widely studied, the mechanisms that control embryo size-and how these mechanisms affect cell fate-remain unknown. Here we use the mouse blastocyst as a model to unravel a key role of fluid-filled lumen in the control of embryo size and specification of cell fate. We find that there is a twofold increase in lumenal pressure during blastocyst development, which translates into a concomitant increase in cell cortical tension and tissue stiffness of the trophectoderm that lines the lumen. Increased cortical tension leads to vinculin mechanosensing and maturation of functional tight junctions, which establishes a positive feedback loop to accommodate lumen growth. When the cortical tension reaches a critical threshold, cell-cell adhesion cannot be sustained during mitotic entry, which leads to trophectoderm rupture and blastocyst collapse. A simple theory of hydraulically gated oscillations recapitulates the observed dynamics of size oscillations, and predicts the scaling of embryo size with tissue volume. This theory further predicts that disrupted tight junctions or increased tissue stiffness lead to a smaller embryo size, which we verified by biophysical, embryological, pharmacological and genetic perturbations. Changes in lumenal pressure and size can influence the cell division pattern of the trophectoderm, and thereby affect cell allocation and fate. Our study reveals how lumenal pressure and tissue mechanics control embryo size at the tissue scale, which is coupled to cell position and fate at the cellular scale.