National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
School of Engineering and Materials Science, Queen Mary University, London, UK.
Nat Commun. 2022 Aug 17;13(1):4832. doi: 10.1038/s41467-022-32102-9.
A fundamental property of higher eukaryotes that underpins their evolutionary success is stable cell-cell cohesion. Yet, how intrinsic cell rheology and stiffness contributes to junction stabilization and maturation is poorly understood. We demonstrate that localized modulation of cell rheology governs the transition of a slack, undulated cell-cell contact (weak adhesion) to a mature, straight junction (optimal adhesion). Cell pairs confined on different geometries have heterogeneous elasticity maps and control their own intrinsic rheology co-ordinately. More compliant cell pairs grown on circles have slack contacts, while stiffer triangular cell pairs favour straight junctions with flanking contractile thin bundles. Counter-intuitively, straighter cell-cell contacts have reduced receptor density and less dynamic junctional actin, suggesting an unusual adaptive mechano-response to stabilize cell-cell adhesion. Our modelling informs that slack junctions arise from failure of circular cell pairs to increase their own intrinsic stiffness and resist the pressures from the neighbouring cell. The inability to form a straight junction can be reversed by increasing mechanical stress artificially on stiffer substrates. Our data inform on the minimal intrinsic rheology to generate a mature junction and provide a springboard towards understanding elements governing tissue-level mechanics.
高等真核生物的一个基本特性是稳定的细胞间黏附,这是它们进化成功的基础。然而,内在细胞流变性和刚性如何有助于连接的稳定和成熟还知之甚少。我们证明了局部调节细胞流变性可以控制松弛、波动的细胞-细胞接触(弱黏附)向成熟、直线连接(最佳黏附)的转变。在不同几何形状上受限的细胞对具有不均匀的弹性图谱,并协调控制自身的内在流变性。在圆上生长的更具弹性的细胞对具有松弛的接触,而更刚性的三角形细胞对则有利于具有侧翼收缩性薄束的直线连接。与直觉相反,更直的细胞-细胞接触具有更低的受体密度和更少的动态连接肌动蛋白,这表明一种不寻常的适应性机械响应来稳定细胞-细胞黏附。我们的模型表明,松弛连接是由于圆形细胞对无法增加自身内在刚性并抵抗来自相邻细胞的压力而产生的。通过在更刚性的基质上人为地增加机械应力,可以逆转不能形成直线连接的情况。我们的数据提供了生成成熟连接所需的最小内在流变性信息,并为理解控制组织水平力学的因素提供了一个跳板。