限制环境下细胞对液体力学的定向反应控制机制

Confinement controls the directional cell responses to fluid forces

Cell Reports

影响因子:6.9

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

DOI: 10.1016/j.celrep.2024.114692

摘要

我们对液体力学如何影响细胞迁移在限制环境中的理解仍然有限。通过将微流控技术与活细胞成像结合，我们证明在紧密限制而非中度限制的空间中，细胞在受到液体力学作用时会逆向反转并逆行向上迁移。这种由液体力学引起的定向变化在细胞表现出较低的机械感应能力、经历较高的水力阻力或感知化学梯度时发生频率较低。细胞逆转需要肌动蛋白聚合向新的细胞前端，正反两方面的数学模拟和实验均证实了这一点。肌动蛋白聚合对于液体力学引发的NHE1激活至关重要，NHE1与钙离子合作，诱导细胞向上迁移。钙离子水平在下游升高，与肌球蛋白IIA的亚细胞分布相一致，其激活增强向上迁移。降低lamin A/C水平促进转移性肿瘤细胞向下迁移，原因是阻止细胞极性建立和细胞内钙离子升高。这一机制可能使癌细胞逃避高压环境，如原发肿瘤。

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.