Matrix obstructions cause multiscale disruption in collective epithelial migration by suppressing leader cell function.
Matrix obstructions cause multiscale disruption in collective epithelial migration by suppressing leader cell function.
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DOI：
10.1091/mbc.e22-06-0226
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发表时间：
2023-08-01
影响因子：
3.3
通讯作者：
Pathak, Amit
中科院分区：
文献类型：
--
作者：
Lee, Ye Lim;Mathur, Jairaj;Walter, Christopher;Zmuda, Hannah;Pathak, Amit
在疾病和发展过程中，细胞外基质的物理变化导致上皮细胞迁移的阻塞、解除阻塞和分散。然而，基质拓扑结构的破坏是否会改变集体细胞迁移速度和细胞-细胞协调仍不清楚。我们微制造的基板与树桩定义的几何形状，密度和方向，这创造了迁移上皮细胞的障碍。在这里，我们表明，细胞失去了他们的速度和方向性时，通过密集的障碍物移动。虽然领导细胞比追随者细胞在平坦的基板上更硬，但密集的障碍物导致整体细胞软化。通过一个基于格子的模型，我们确定细胞突起，细胞间粘附，和领导者-追随者的通信作为障碍敏感的集体细胞迁移的关键机制。我们的建模预测和实验验证表明，细胞的阻塞敏感性需要细胞-细胞粘附和突起的最佳平衡。MDCK（更具粘性）和α-连环蛋白缺失的MCF 10A细胞的阻塞敏感性均低于野生型MCF 10A细胞。微尺度软化、中尺度紊乱和大尺度多细胞通讯使上皮细胞群体能够感知在具有挑战性的环境中遇到的拓扑障碍。因此，阻塞敏感性可以定义集体迁移但仍保持细胞间通讯的细胞的“机械型”。
During disease and development, physical changes in extracellular matrix cause jamming, unjamming, and scattering in epithelial migration. However, whether disruptions in matrix topology alter collective cell migration speed and cell–cell coordination remains unclear. We microfabricated substrates with stumps of defined geometry, density, and orientation, which create obstructions for migrating epithelial cells. Here, we show that cells lose their speed and directionality when moving through densely spaced obstructions. Although leader cells are stiffer than follower cells on flat substrates, dense obstructions cause overall cell softening. Through a lattice-based model, we identify cellular protrusions, cell–cell adhesions, and leader–follower communication as key mechanisms for obstruction-sensitive collective cell migration. Our modeling predictions and experimental validations show that cells’ obstruction sensitivity requires an optimal balance of cell–cell adhesions and protrusions. Both MDCK (more cohesive) and α-catenin–depleted MCF10A cells were less obstruction sensitive than wild-type MCF10A cells. Together, microscale softening, mesoscale disorder, and macroscale multicellular communication enable epithelial cell populations to sense topological obstructions encountered in challenging environments. Thus, obstruction–sensitivity could define “mechanotype” of cells that collectively migrate yet maintain intercellular communication.