Confinement controls the directional cell responses to fluid forces

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

Confinement controls the directional cell responses to fluid forces

Cell Rep. 2024 Aug 28;43(9):114692. doi: 10.1016/j.celrep.2024.114692. Online ahead of print.

Authors

Affiliations

¹ Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA.
² Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA.
³ Materials Research and Education Center, Auburn University, Auburn, AL 36849, USA.
⁴ Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA; Center for Pharmacogenomics and Single-Cell Omics (AUPharmGx), Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA; UAB O'Neal Comprehensive Cancer, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35233, USA.
⁵ Department of Biomedical Engineering, Binghamton University, SUNY, Binghamton, NY 13902, USA.
⁶ Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA. Electronic address: pmistriotis@auburn.edu.

PMID: 39207902
DOI: 10.1016/j.celrep.2024.114692

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.

Keywords: CP: Cell biology; NHE1; actin polymerization; actomyosin contractility; cancer metastasis; chemotaxis; confined migration; hydraulic resistance; mechanosensitive ion channels; nuclear stiffness; upstream migration.

Abstract

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