Traction Forces Control Cell-Edge Dynamics and Mediate Distance Sensitivity during Cell Polarization
Zeno Messi, Alicia Bornert, Franck Raynaud, Alexander B. Verkhovsky
Abstract
Traction forces are generated by cellular actin-myosin system and transmitted to the environment through adhesions. They are believed to drive cell motion, shape changes, and extracellular matrix remodeling [1Schwarz U.S. Gardel M.L. United we stand: integrating the actin cytoskeleton and cell-matrix adhesions in cellular mechanotransduction.J. Cell Sci. 2012; 125: 3051-3060Crossref PubMed Scopus (256) Google Scholar, 2Polacheck W.J. Chen C.S. Measuring cell-generated forces: a guide to the available tools.Nat. Methods. 2016; 13: 415-423Crossref PubMed Scopus (291) Google Scholar, 3Nerger B.A. Siedlik M.J. Nelson C.M. Microfabricated tissues for investigating traction forces involved in cell migration and tissue morphogenesis.Cell. Mol. Life Sci. 2017; 74: 1819-1834Crossref PubMed Scopus (14) Google Scholar]. 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Balance between cell-substrate adhesion and myosin contraction determines the frequency of motility initiation in fish keratocytes.Proc. Natl. Acad. Sci. USA. 2015; 112: 5045-5050Crossref PubMed Scopus (71) Google Scholar]. Here, we analyze the dynamics of traction forces during the protrusion-retraction cycle of polarizing fish epidermal keratocytes and find that forces fluctuate together with the cycle, increasing during protrusion and reaching maximum at the beginning of retraction. We relate force dynamics to the recently discovered phenomenological rule [16Raynaud F. Ambühl M.E. Gabella C. Bornert A. Sbalzarini I.F. Meister J.-J. Verkhovsky A.B. Minimal model for spontaneous cell polarization and edge activity in oscillating, rotating and migrating cells.Nat. Phys. 2016; 12: 367-373Crossref Scopus (23) Google Scholar] that governs cell-edge behavior during keratocyte polarization: both traction forces and probability of switch from protrusion to retraction increase with the distance from the cell center. Diminishing forces with cell contractility inhibitor leads to decreased edge fluctuations and abnormal polarization, although externally applied force can induce protrusion-retraction switch. These results suggest that forces mediate distance sensitivity of the edge dynamics and organize cell-edge behavior, leading to spontaneous polarization. Actin flow rate did not exhibit the same distance dependence as traction stress, arguing against its role in organizing edge dynamics. Finally, using a simple model of actin-myosin network, we show that force-distance relationship might be an emergent feature of such networks.