Long-range topotaxis as a result of supercellular topographic anisotropy during chemotaxis

Highly motile cells, like patrolling leukocytes during immune response and amoeboid sarcoma cells during metastasis, navigate relatively long distances in complex environments where they encounter a wide variety of topographic structures on different length scales. Subcellular topographic substrate anisotropies have been shown to cause a drift in cell migration (topotaxis) , indicating that the topography of the extracellular environment can function as a physical guidance cue. Here, we expand on these previously reported subcellular findings by showing that supercellular asymmetries spanning long distances can also induce topotactic drift. Such long-range topotactic drift was generated by exposing highly motile cells to a subtle spatial gradient in the arrangement of cell-sized pillars. Using an analytical model and mean first-passage time analyses, we show that this type of long-range topotaxis emerges through the many interactions of persistently random migrating cells with the anisotropic confinement imposed by the gradient pillar field. We demonstrate that pillar-induced long-range topotaxis is conserved during chemotaxis, the cellular drift in response to chemical gradients. Topotactic and chemotactic drifts were found to add linearly, a finding that could have implications for studies on directed cell migration, which mostly focus on chemotactic responses alone. Moreover, as long-range topotaxis is an independent physical effect, it offers a way to steer highly motile cells independently from chemotactic guidance, which could have potential applications in cell sorting and tissue engineering.