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Mechanochemical self-organization determines search pattern in migratory cells


To reach their destination, migrating cells rely on polarized signal inputs to align the direction of their motion. However, navigational guidance cues are not always present, which establishes the need for exploratory search mechanisms in cells seeking signal inputs. Here, we investigate how non-Brownian search patterns emerge in adherent vertebrate cells. Combining experimental and theoretical analysis, we demonstrate that nanoscale plasma membrane deformations nucleate a mechanochemical feedback loop that mediates longevity of the cell’s leading edge, a necessary requirement for directed cell migration. We further observe stochastic transitions between phases of random and persistent cell motion, whereby the mechanochemical circuit augments cell persistence and search area. Collectively, these findings are consistent with a self-organizing system for a superdiffusive pattern of motion that is spontaneously employed by migratory cells in the absence of external signal inputs.

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The data that support the findings of this study are available from the corresponding author on reasonable request. No restrictions apply.

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We would like to thank A. Ricker, K. Tkotz, J. Lehrich, A. Bodzeta, H. Nüsse and S. Kohaus for excellent technical assistance and N. Gov for insightful discussions on the force model. Special thanks go to R. Kurre from the integrated Bioimaging Facility Osnabrueck (iBIOs, University of Osnabrück) for help with LLM. This work was supported by funds from the DFG to M.G. (EXC-1003; GA 2268/2-1, CRC1348/A06, CRC944/P22), M.M. (EXC-1003/FF-2015-07), J.K. (CRC1348/A02, CRC944/P5) and V.G. (CRC1348/A04, CRC1009/A06) and the Medical Faculty of the University of Münster to M.G. (IMF IGA-121610) and M.M. (IZKF Mat2/019/16).

Author information

I.B. performed all experimental work, except experiments with HUVEC cells and polyacrylamide gels. T.S. and I.B. developed image analysis software with input from M.M. and M.G. T.S. and I.B. performed optical tweezer experiments. T.S., L.L. and I.R. prepared mathematical models with input from I.B. and M.G. I.R. and B.T. performed polyacrylamide gel experiments. D.G., L.G., M.M. and V.G. performed HUVEC experiments. L.G. and M.M. performed quantitative PCR experiments. C.R., U.K. and J.K. prepared SEM images. I.B. and M.G. designed experiments, discussed results and wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing interests.

Correspondence to M. Galic.

Supplementary Information

Supplementary Information

Supplementary Information, Supplementary Figures 1–6 and Supplementary References 1–84.

Reporting Summary

Supplementary Video 1

Single-cell trace depicting two-mode migration. NIH 3T3 cell was transfected with a cytosolic reference. Centre of mass is used to determine cell trace. Scale bar is 20 µm.

Supplementary Video 2

Lattice lightsheet of NIH 3T3 fibroblast. NIH 3T3 cell was transfected with f-tractin and imaged using LLM. Note extension–retraction cycles at the leading edge. Scale bar is 10 µm.

Supplementary Video 3

Lattice lightsheet of seed-like structure at retracting lamellipodium. NIH 3T3 cell transfected with f-tractin and imaged using LLM. Nascent lamellipodium appears at the base of retracting lamellipodium. Scale bar is 5 µm.

Supplementary Video 4

Lattice lightsheet of biosensor versus actin at leading edge. NIH 3T3 cell transfected with f-tractin (green) and biosensor (magenta), imaged using LLM. Videos depict 3D reconstruction (left), x/z re-slice (middle) and x/y re-slice (right). Scale bar (left, right) 5 µm, (middle) 2 µm.

Supplementary Video 5

Lattice lightsheet of biosensor versus paxillin at leading edge. NIH 3T3 fibroblast transfected with the FA marker paxillin (green) and the curvature-sensitive biosensor (magenta). Videos depict 3D reconstruction (left), x/z re-slice (middle) and x/y re-slice (right). Scale bar (left) 5 µm, (middle, right) 2 µm.

Supplementary Video 6

Minimal model of LE re-initiation. From left to right, simulation with default settings, in the absence of myosin-dependent pulling forces, in the absence of positive feedback loop and in the absence of adhesion.

Supplementary Video 7

Addition of ML-7 aborts lamellipodial re-initiation. Cell was transfected with a marker for filamentous actin (f-tractin). Note the loss of lamellipodial extension–retraction cycles, but not of stress fibres, on addition of ML-7. Scale bar is 20 µm.

Supplementary Video 8

Cell plated on Y-shaped micropattern shows continuous lamellipodium surrounding the whole cell. Cell plated on fibronectin-coated Y-shaped micropattern and transfected with f-tractin (red) and a cytosolic reference (green). Note lamellipodium enclosing the whole cell circumference. Scale bar is 10 µm.

Supplementary Video 9

Massive overexpression of I-BAR domain alters migration pattern. NIH 3T3 cells were transfected with a cytosolic marker (left) or the I-BAR domain (right) and imaged 20 h post-transfection. Scale bar is 20 µm.

Supplementary Video 10

Transition of migration pattern with increase of I-BAR levels. Starting 5 h post-transfection, images of NIH 3T3 cell transfected with I-BAR domain were taken for 15 h. Note loss of motion persistence as I-BAR levels increase with time. Scale bar is 20 µm.

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Fig. 1: Lamellipodial and migration dynamics of NIH 3T3 cells.
Fig. 2: Curvature-dependent self-organization drives lamellipodial re-initiation at the leading edge.
Fig. 3: Theoretical model and experimental validation of self-organizing system.
Fig. 4: Artificial PM deformations trigger activation of self-organizing system.
Fig. 5: Self-organizing system determines motion persistence and search area in NIH 3T3 fibroblasts.
Fig. 6: Self-organizing system determines motion persistence and search area in neutrophil-like PLB-985 cells.