限制控制对流体力的定向细胞反应
Confinement controls the directional cell responses to fluid forces
影响因子:6.90000
分区:生物学1区 Top / 细胞生物学2区
发表日期:2024 Sep 24
作者:
Farshad Amiri, Ayuba A Akinpelu, William C Keith, Farnaz Hemmati, Ravi S Vaghasiya, Dylan Bowen, Razan S Waliagha, Chuanyu Wang, Pengyu Chen, Amit K Mitra, Yizeng Li, Panagiotis Mistriotis
摘要
我们对流体力如何影响细胞迁移的理解仍然有限。通过将微流体与活细胞成像整合在一起，我们证明了紧密的细胞，但不是中等限制的空间，并在暴露于流体力时向上移动。当细胞表现出降低的机械强度，液压抗性升高或感知化学梯度时，这种流体力诱导的方向变化的频率较小。细胞逆转需要肌动蛋白聚合到新的细胞界，如数学和实验表所示。肌动蛋白聚合对于流体力诱导的NHE1激活是必需的，NHE1与钙合作以诱导上游迁移。钙水平在下游增加，反映了肌球蛋白IIA的亚细胞分布，其激活增强了上游迁移。减少的层粘连蛋白A/C水平通过预防细胞极性建立和细胞内钙升高来促进转移性肿瘤细胞的下游迁移。这种机制可以使癌细胞逃避高压环境，例如原发性肿瘤。
Abstract
Our understanding of how fluid forces influence cell migration in confining environments remains limited. By integrating microfluidics with live-cell imaging, we demonstrate that cells in tightly-but not moderately-confined spaces reverse direction and move upstream upon exposure to fluid forces. This fluid force-induced directional change occurs less frequently when cells display diminished mechanosensitivity, experience elevated hydraulic resistance, or sense a chemical gradient. Cell reversal requires actin polymerization to the new cell front, as shown mathematically and experimentally. Actin polymerization is necessary for the fluid force-induced activation of NHE1, which cooperates with calcium to induce upstream migration. Calcium levels increase downstream, mirroring the subcellular distribution of myosin IIA, whose activation enhances upstream migration. Reduced lamin A/C levels promote downstream migration of metastatic tumor cells by preventing cell polarity establishment and intracellular calcium rise. This mechanism could allow cancer cells to evade high-pressure environments, such as the primary tumor.