Adaptive force transmission in amoeboid cell migration

Abstract

The leading front of a cell can either protrude as an actin-free membrane bleb that is inflated by actomyosin-driven contractile forces, or as an actin-rich pseudopodium, a site where polymerizing actin filaments push out the membrane1,2,3. Pushing filaments can only cause the membrane to protrude if the expanding actin network experiences a retrograde counter-force, which is usually provided by transmembrane receptors of the integrin family4. Here we show that chemotactic dendritic cells mechanically adapt to the adhesive properties of their substrate by switching between integrin-mediated and integrin-independent locomotion. We found that on engaging the integrin–actin clutch, actin polymerization was entirely turned into protrusion, whereas on disengagement actin underwent slippage and retrograde flow. Remarkably, accelerated retrograde flow was balanced by an increased actin polymerization rate; therefore, cell shape and protrusion velocity remained constant on alternating substrates. Due to this adaptive response in polymerization dynamics, tracks of adhesive substrate did not dictate the path of the cells. Instead, directional guidance was exclusively provided by a soluble gradient of chemoattractant, which endowed these 'amoeboid' cells with extraordinary flexibility, enabling them to traverse almost every type of tissue.

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Figure 1: Spatial and temporal dynamics of actin and myosin II in migrating dendritic cells.
Figure 2: Dendritic cells can use integrins for transmembrane force coupling, and uncoupling enhances retrograde actin flow without affecting migration.
Figure 3: Actin polymerization rate is variable in the molecular clutch system.
Figure 4: Leading edge protrusion and chemotactic movement is substrate-independent.

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Acknowledgements

We thank S. Cremer for statistical analysis, K. Hirsch for technical assistance, D. Critchley for talin1-deficient mice and R. Fässler for integrin-deficient mice, discussions and critical reading of the manuscript. This work was supported by the German Research Foundation, the Peter Hans Hofschneider Foundation for Experimental Biomedicine, the Max Planck Society, the Alexander von Humboldt Foundation and the allergology programme of the Landesstiftung Baden-Württemberg.

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J.R. and M.S. designed, performed and analysed experiments and wrote the manuscript. K.S., M.W., T.L. and H.P. performed experiments, M.P. contributed ideas and J.P. and J.P.S. provided passivated surfaces.

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Correspondence to Michael Sixt.

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The authors declare no competing financial interests.

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Renkawitz, J., Schumann, K., Weber, M. et al. Adaptive force transmission in amoeboid cell migration. Nat Cell Biol 11, 1438–1443 (2009). https://doi.org/10.1038/ncb1992

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