Highlights d SCHEEPDOG programs electrical cues to herd cell migration via ''electrotaxis'' d Programmable electrical control allows cellular groups to perform any 2D maneuver d Precise control is possible because cells time-average x-and y-electric fields d Electrotaxis occurs across many cell types and species and can be a powerful tool
As collective cell migration is essential in biological processes spanning development, healing, and cancer progression, methods to externally program cell migration are of great value. However, problems can arise if the external commands compete with strong, preexisting collective behaviors in the tissue or system. We investigate this problem by applying a potent external migratory cue—electrical stimulation and electrotaxis—to primary mouse skin monolayers where we can tune cell–cell adhesion strength to modulate endogenous collectivity. Monolayers with high cell–cell adhesion showed strong natural coordination and resisted electrotactic control, with this conflict actively damaging the leading edge of the tissue. However, reducing preexisting coordination in the tissue by specifically inhibiting E-cadherin–dependent cell–cell adhesion, either by disrupting the formation of cell–cell junctions with E-cadherin–specific antibodies or rapidly dismantling E-cadherin junctions with calcium chelators, significantly improved controllability. Finally, we applied this paradigm of weakening existing coordination to improve control and demonstrate accelerated wound closure in vitro. These results are in keeping with those from diverse, noncellular systems and confirm that endogenous collectivity should be considered as a key quantitative design variable when optimizing external control of collective migration.
Directed cell migration is critical across biological processes spanning healing to cancer invasion, yet no tools allow such migration to be interactively guided. We present a new bioreactor that harnesses electrotaxis-directed cell migration along electric field gradients-by integrating multiple independent electrodes under computer control to dynamically program electric field patterns, and hence steer cell migration. Using this platform, we programmed and characterized multiple precise, two-dimensional collective migration maneuvers in renal epithelia and primary skin keratinocyte ensembles. First, we demonstrated on-demand, 90-degree collective turning. Next, we developed a universal electrical stimulation scheme capable of programming arbitrary 2D migration maneuvers such as precise angular turns and directing cells to migrate in a complete circle. Our stimulation scheme proves that cells effectively timeaverage electric field cues, helping to elucidate the transduction time scales in electrotaxis. Together, this work represents a fundamentally different platform for controlling cell migration with broad utility across fields.
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