Abstract
In wound healing and development, large epithelial sheets migrate collectively, in defined directions, and maintain tight cell–cell adhesion. This type of movement ensures an essential function of epithelia, a barrier, which is lost when cells lose connection and move in isolation. Unless wounded, epithelial sheets in cultures normally do not have overall directional migration. Cell migration is mostly studied when cells are in isolation and in the absence of mature cell–cell adhesion; the mechanisms of the migration of epithelial sheets are less well understood. We used small electric fields (EFs) as a directional cue to instigate and guide migration of epithelial sheets. Significantly, cells in monolayer migrated far more efficiently and directionally than cells in isolation or smaller cell clusters. We demonstrated for the first time the group size-dependent directional migratory response in several types of epithelial cells. Gap junctions made a minimal contribution to the directional collective migration. Breaking down calcium-dependent cell–cell adhesion significantly reduced directional sheet migration. Furthermore, E-cadherin blocking antibodies abolished migration of cell sheets. Traction force analysis revealed an important role of forces that cells in the leading rows exert on the substratum. With EF, the traction forces of the leading edge cells coordinated in directional re-orientation. Our study thus identifies a novel mechanism—E-cadherin dependence and coordinated traction forces of leading cells in collective directional migration of large epithelial sheets.
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Acknowledgments
This work was supported by NIH 1R01EY019101. M.Z. is also supported by grants from NSF MCB-0951199, and California Institute of Regenerative Medicine RB1-01417, UC Davis Dermatology Developmental fund. L.L. and J.X.J. are supported by Key Program of National Nature Science Foundation of China (81030037) and Open fund of State Key Laboratory of Trauma, Burns and Combined Injury (SKLZZ200804). L.L. is also supported by China Scholarship Council. T.H. and S.Y. are supported by NIH R01GM094798 and a Beckman Young Investigator Award (to S.Y.). We thank Lillian Diep for assistance with the analysis of some of the videos, and Arisa Uemura for the scanning electron micrograph of pillar substrates.
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Video S1 Collective electrotaxis of MDCK II cells in monolayer, but not in isolation. Time is in hh:mm style. (MPG 1484 kb)
Video S2 MDCK II cell sheets respond to EFs in a size-dependent manner. Time is in hh:mm style. (MPG 1484 kb)
Video S3 Better collective electrotaxis in monolayer than in isolation in various types of cells. Time is in hh:mm style. (MPG 585 kb)
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Video S4 E-cadherin mediated cell-cell adhesion is required for EF-guiding migration of MDCK I cells in a monolayer. Time is in hh:mm style. (MPG 1484 kb)
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Video S5 Traction force re-orientation at the leading edges of cell groups in an EF. Time is in hh:mm style. (MPG 2312 kb)
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Li, L., Hartley, R., Reiss, B. et al. E-cadherin plays an essential role in collective directional migration of large epithelial sheets. Cell. Mol. Life Sci. 69, 2779–2789 (2012). https://doi.org/10.1007/s00018-012-0951-3
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DOI: https://doi.org/10.1007/s00018-012-0951-3