Cao Xuan, Moeendarbary Emad, Isermann Philipp, Davidson Patricia M, Wang Xiao, Chen Michelle B, Burkart Anya K, Lammerding Jan, Kamm Roger D, Shenoy Vivek B
Department of Materials Science and Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, Pennsylvania.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Mechanical Engineering, University College London, London, United Kingdom.
Biophys J. 2016 Oct 4;111(7):1541-1552. doi: 10.1016/j.bpj.2016.08.011.
It is now evident that the cell nucleus undergoes dramatic shape changes during important cellular processes such as cell transmigration through extracellular matrix and endothelium. Recent experimental data suggest that during cell transmigration the deformability of the nucleus could be a limiting factor, and the morphological and structural alterations that the nucleus encounters can perturb genomic organization that in turn influences cellular behavior. Despite its importance, a biophysical model that connects the experimentally observed nuclear morphological changes to the underlying biophysical factors during transmigration through small constrictions is still lacking. Here, we developed a universal chemomechanical model that describes nuclear strains and shapes and predicts thresholds for the rupture of the nuclear envelope and for nuclear plastic deformation during transmigration through small constrictions. The model includes actin contraction and cytosolic back pressure that squeeze the nucleus through constrictions and overcome the mechanical resistance from deformation of the nucleus and the constrictions. The nucleus is treated as an elastic shell encompassing a poroelastic material representing the nuclear envelope and inner nucleoplasm, respectively. Tuning the chemomechanical parameters of different components such as cell contractility and nuclear and matrix stiffnesses, our model predicts the lower bounds of constriction size for successful transmigration. Furthermore, treating the chromatin as a plastic material, our model faithfully reproduced the experimentally observed irreversible nuclear deformations after transmigration in lamin-A/C-deficient cells, whereas the wild-type cells show much less plastic deformation. Along with making testable predictions, which are in accord with our experiments and existing literature, our work provides a realistic framework to assess the biophysical modulators of nuclear deformation during cell transmigration.
现在很明显，在诸如细胞通过细胞外基质和内皮进行迁移等重要细胞过程中，细胞核会发生显著的形状变化。最近的实验数据表明，在细胞迁移过程中，细胞核的可变形性可能是一个限制因素，并且细胞核所经历的形态和结构改变会扰乱基因组组织，进而影响细胞行为。尽管其很重要，但仍缺乏一个生物物理模型，该模型能将实验观察到的细胞核形态变化与在通过小收缩处迁移过程中的潜在生物物理因素联系起来。在此，我们开发了一个通用的化学力学模型，该模型描述了核应变和形状，并预测了在通过小收缩处迁移过程中核膜破裂和核塑性变形的阈值。该模型包括肌动蛋白收缩和胞质背压，它们通过收缩挤压细胞核，并克服来自细胞核和收缩处变形的机械阻力。细胞核被视为一个弹性壳，分别包围着代表核膜和内核质的多孔弹性材料。通过调整不同组分的化学力学参数，如细胞收缩性以及核和基质的刚度，我们的模型预测了成功迁移的收缩尺寸下限。此外，将染色质视为塑性材料，我们的模型如实地再现了实验观察到的在缺乏核纤层蛋白A/C的细胞中迁移后不可逆的核变形，而野生型细胞的塑性变形则小得多。除了做出与我们的实验和现有文献一致的可测试预测外，我们的工作还提供了一个现实的框架，以评估细胞迁移过程中核变形的生物物理调节因子。
