Mechanical constraints to cell-cycle progression in a pseudostratified epithelium.
Mechanical constraints to cell-cycle progression in a pseudostratified epithelium.
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DOI：
10.1016/j.cub.2022.03.004
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发表时间：
2022-05-09
期刊：
影响因子：
--
通讯作者：
Vincent JP
中科院分区：
文献类型：
--
作者：
Hecht S;Perez-Mockus G;Schienstock D;Recasens-Alvarez C;Merino-Aceituno S;Smith M;Salbreux G;Degond P;Vincent JP
当器官和组织在发育或再生过程中接近正常大小时，生长减慢，细胞增殖逐渐停止。在促进生长终止的各种过程中，可能通过粘附连接的机械反馈被认为发挥了作用。然而，由于粘附连接仅存在于根尖下区域的一个狭窄平面上，因此可能需要其他结构来感知沿根尖-基底（a -b）轴的机械应力，特别是在厚的假分层上皮中。这可以通过细胞核来实现，它与组织培养中的机械转导有关。此外，核拥挤和空间限制施加的机械约束可能会影响核互动迁移（IKNM），这使得G2核能够到达顶端表面，在那里它们通常进行有丝分裂。为了探索机械约束如何影响IKNM，我们设计了一个基于个体的模型，该模型将细胞核视为受细胞皮层和其他细胞核存在约束的可变形物体。该模型预测了生长过程中细胞周期相比例的变化，我们用细胞周期相报告因子FUCCI（荧光泛素化细胞周期指示器）对其进行了验证。然而，该模型并不排除无限生长，这导致我们假设细胞核必须基本迁移才能获得S相进入所需的假定基础信号。通过这种改进，我们更新的模型解释了观察到的生长逐渐减慢，并解释了假分层上皮如何在生长完成后达到典型厚度。
As organs and tissues approach their normal size during development or regeneration, growth slows down, and cell proliferation progressively comes to a halt. Among the various processes suggested to contribute to growth termination, mechanical feedback, perhaps via adherens junctions, has been suggested to play a role. However, since adherens junctions are only present in a narrow plane of the subapical region, other structures are likely needed to sense mechanical stresses along the apical-basal (A-B) axis, especially in a thick pseudostratified epithelium. This could be achieved by nuclei, which have been implicated in mechanotransduction in tissue culture. In addition, mechanical constraints imposed by nuclear crowding and spatial confinement could affect interkinetic nuclear migration (IKNM), which allows G2 nuclei to reach the apical surface, where they normally undergo mitosis. To explore how mechanical constraints affect IKNM, we devised an individual-based model that treats nuclei as deformable objects constrained by the cell cortex and the presence of other nuclei. The model predicts changes in the proportion of cell-cycle phases during growth, which we validate with the cell-cycle phase reporter FUCCI (Fluorescent Ubiquitination-based Cell Cycle Indicator). However, this model does not preclude indefinite growth, leading us to postulate that nuclei must migrate basally to access a putative basal signal required for S phase entry. With this refinement, our updated model accounts for the observed progressive slowing down of growth and explains how pseudostratified epithelia reach a stereotypical thickness upon completion of growth.
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