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Nuclear and cellular mechanics: Implications for laminopathies and cancer.

机译：核和细胞力学：对椎间盘突出症和癌症的影响。

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Understanding cell mechanics in the context of cellular processes is essential as the constitutive cells in the human body are constantly subjected to mechanical stresses and often presented with situations where cellular adaptations are critical for their proliferation. For example, during wound healing, the initial onset of wounding causes cells residing in the extravascular space to be subjected to mechanical shear stress from vascular blood flow. Subsequent loss of cell-cell contacts may cause epithelial cells to undergo epithelial-mesenchymal transition (EMT), a process that turns the cells more fibroblast-like, changing not only morphology, but also increasing motility. Mechanical adaptations in response to shear stress or to increase cellular migration have been studied mainly though visualization of changes in cytoskeletal structures and understanding the corresponding signaling pathways. These observations are informative in elucidating regulating proteins and cellular phenotype, but do not offer insights to the effects of these cellular changes and regulations. A few important questions remain: (1) what are the corresponding mechanical changes, (2) how do these mechanical changes help the cell adapt, (3) is it possible these adaptations result in unforeseen consequences, and (4) if so, do they result in disease?; Due to technical limitations, only a portion of the answers have been explored to date. In an attempt to answer these questions, we examine changes in intracellular and intranuclear mechanics as a result of changes in cytoskeletal organization. We also document consequences of these changes, such as difference in cell migration, nucleus movement, and centrosome polarity. By first observing Swiss 3T3 fibroblasts, the quintessential cytoskeletal model system, we were able to develop original assays and gain an extensive foundation of knowledge. We reveal that adherent cells subjected to fluid shear stress strengthen their cytoskeleton and identify Rho-kinase as a key factor in the mechanotransduction pathway that controls the cytoskeleton mechanical response of cells to shear. In addition, we establish Cdc42 as a molecular regulator of shear induced microtubule-dependent polarity-driven nucleus movement in Swiss 3T3 fibroblasts.; We then applied this knowledge to further understand the role of cellular mechanics, beyond that of wound healing, in human diseases. For laminopathies, we examined lamin A/C knockout mouse embryo fibroblasts and find that intracellular mechanics depends critically on the integrity of the nuclear lamina. Loss of lamin A/C perturbed both cell motility and polarization, suggesting the existence of a functional connection between the nucleus and the cytoskeleton. In addition, preliminary data indicates that cell mechanics may be used, in conjunction with further tests of RhoGTPase mediation of EMT and migration pathways, to offer an alternative pathogenesis of high grade ovarian cancer.
机译：了解细胞过程中的细胞力学是必不可少的，因为人体中的组成性细胞会不断受到机械应力的作用，并且经常出现细胞适应对其增殖至关重要的情况。例如，在伤口愈合期间，伤口的初始发作使驻留在血管外空间中的细胞经受来自血管血流的机械剪切应力。随后细胞与细胞间接触的丧失可能导致上皮细胞经历上皮-间质转化（EMT），这一过程使细胞变得更像成纤维细胞样，不仅改变了形态，而且还提高了运动能力。主要通过可视化的细胞骨架结构变化和理解相应的信号传导途径来研究响应剪切应力或增加细胞迁移的机械适应性。这些观察结果有助于阐明调节蛋白和细胞表型，但未提供对这些细胞变化和调节作用的见解。还有一些重要的问题：（1）相应的机械变化是什么；（2）这些机械变化如何帮助细胞适应；（3）这些适应是否可能导致无法预料的后果；（4）如果是，则他们会导致疾病吗？由于技术限制，到目前为止，仅对部分答案进行了探讨。为了回答这些问题，我们研究了由于细胞骨架组织变化而引起的细胞内和核内力学变化。我们还记录了这些变化的后果，例如细胞迁移，核运动和中心体极性的差异。通过首先观察瑞士3T3成纤维细胞（典型的细胞骨架模型系统），我们能够开发原始的测定方法并获得广泛的知识基础。我们发现，受到流体剪切应力作用的贴壁细胞会增强其细胞骨架，并确定Rho激酶是控制细胞对剪切的细胞骨架机械反应的机械转导途径中的关键因素。此外，我们将Cdc42建立为瑞士3T3成纤维细胞中剪切诱导的微管依赖性极性驱动的核运动的分子调节剂。然后，我们运用这些知识进一步了解了细胞力学在人类疾病中的作用，而不仅仅是伤口愈合。对于lamopathies，我们检查了lamin A / C基因敲除小鼠胚胎成纤维细胞，发现细胞内机制在很大程度上取决于核层板的完整性。核纤层蛋白A / C的丧失会扰乱细胞的运动性和极化作用，表明核与细胞骨架之间存在功能连接。此外，初步数据表明，可以结合使用细胞力学与RhoGTPase介导的EMT和迁移途径的进一步测试，来提供高级卵巢癌的另一种发病机制。

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