Cellular and Molecular Bioengineering

, Volume 8, Issue 2, pp 247–257 | Cite as

Collective Migration Exhibits Greater Sensitivity But Slower Dynamics of Alignment to Applied Electric Fields

  • Mark L. Lalli
  • Anand R. AsthagiriEmail author


During development and disease, cells migrate collectively in response to gradients in physical, chemical and electrical cues. Despite its physiological significance and potential therapeutic applications, electrotactic collective cell movement is relatively less well understood. Here, we analyze the combined effect of intercellular interactions and electric fields on the directional migration of non-transformed mammary epithelial cells, MCF-10A. Our data show that clustered cells exhibit greater sensitivity to applied electric fields but align more slowly than isolated cells. Clustered cells achieve half-maximal directedness with an electric field that is 50% weaker than that required by isolated cells; however, clustered cells take ~2–4 fold longer to align. This trade-off in greater sensitivity and slower dynamics correlates with the slower speed and intrinsic directedness of collective movement even in the absence of an electric field. Whereas isolated cells exhibit a persistent random walk, the trajectories of clustered cells are more ballistic as evidenced by the superlinear dependence of their mean square displacement on time. Thus, intrinsically-directed, slower clustered cells take longer to redirect and align with an electric field. These findings help to define the operating space and the engineering trade-offs for using electric fields to affect cell movement in biomedical applications.


Cell–cell interactions Directional bias Electrotaxis Persistence 



We thank the members of the Asthagiri group for helpful discussions. This work was supported by the National Institutes of Health grant R01CA138899 and start-up resources provided by Northeastern University.

Conflict of interest

Mark L. Lalli and Anand R. Asthagiri declare that they have no conflict of interest.

Ethical Standards

No human or animal studies were carried out by the authors for this article.

Supplementary material

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Supplementary material 1 (PDF 684 kb)

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Supplementary material 3 (AVI 170834 kb)

Supplementary material 4 (AVI 166154 kb)

Supplementary material 5 (AVI 170834 kb)


  1. 1.
    Adams, D. S., and M. Levin. Endogenous voltage gradients as mediators of cell-cell communication: strategies for investigating bioelectrical signals during pattern formation. Cell Tissue Res. 352:95–122, 2013.CrossRefGoogle Scholar
  2. 2.
    Bai, H., C. D. McCaig, J. V. Forrester, and M. Zhao. DC electric fields induce distinct preangiogenic responses in microvascular and macrovascular cells. Arterioscler. Thromb. Vasc. Biol. 24:1234–1239, 2004.CrossRefGoogle Scholar
  3. 3.
    Berens, P. J. CircStat: a MATLAB toolbox for circular statistics. Stat. Softw. 31:1–21, 2009.MathSciNetGoogle Scholar
  4. 4.
    Carey, S. P., A. Starchenko, A. L. McGregor, and C. A. Reinhart-King. Leading malignant cells initiate collective epithelial cell invasion in a three-dimensional heterotypic tumor spheroid model. Clin. Exp. Metastasis 30:615–630, 2013.CrossRefGoogle Scholar
  5. 5.
    Conant, C. G., J. T. Nevill, M. Schwartz, and C. Ionescu-Zanetti. Wound healing assays in well plate–coupled microfluidic devices with controlled parallel flow. J. Assoc. Lab. Autom. 15:52–57, 2010.CrossRefGoogle Scholar
  6. 6.
    Cuzick, J., R. Holland, V. Barth, R. Davies, M. Faupel, I. Fentiman, H. J. Frischbier, J. L. LaMarque, M. Merson, V. Sacchini, D. Vanel, and U. Veronesi. Electropotential measurements as a new diagnostic modality for breast cancer. Lancet 352:359–363, 1998.CrossRefGoogle Scholar
  7. 7.
    Debruyne, P. R., E. A. Bruyneel, I.-M. Karaguni, X. Li, G. Flatau, O. Müller, A. Zimber, C. Gespach, and M. M. Mareel. Bile acids stimulate invasion and haptotaxis in human colorectal cancer cells through activation of multiple oncogenic signaling pathways. Oncogene 21:6740–6750, 2002.CrossRefGoogle Scholar
  8. 8.
    Djamgoz, M. B. A., M. Mycielska, Z. Madeja, S. P. Fraser, and W. Korohoda. Directional movement of rat prostate cancer cells in direct-current electric field: involvement of voltage gated Na+ channel activity. J. Cell Sci. 114:2697–2705, 2001.Google Scholar
  9. 9.
    Einstein, A. Über die von der molekularkinetischen Theorie der Wärme geforderte Bewegung von in ruhenden Flüssigkeiten suspendierten Teilchen. Ann. Phys. 322:549–560, 1905.CrossRefGoogle Scholar
  10. 10.
    Fogg, V. C., C.-J. Liu, and B. Margolis. Multiple regions of Crumbs3 are required for tight junction formation in MCF10A cells. J. Cell Sci. 118:2859–2869, 2005.CrossRefGoogle Scholar
  11. 11.
    Foulds, A. T., and I. S. Barker. Human skin battery potentials and their possible role in wound healing. Br. J. Dermatol 109:515–522, 1983.CrossRefGoogle Scholar
  12. 12.
    Gibot, L., L. Wasungu, J. Teissié, and M.-P. Rols. Antitumor drug delivery in multicellular spheroids by electropermeabilization. J. Control. Release 167:138–147, 2013.CrossRefGoogle Scholar
  13. 13.
    Huang, C.-W., J.-Y. Cheng, M.-H. Yen, and T.-H. Young. Electrotaxis of lung cancer cells in a multiple-electric-field chip. Biosens. Bioelectron. 24:3510–3516, 2009.CrossRefGoogle Scholar
  14. 14.
    Kim, J.-H., L. J. Dooling, and A. R. Asthagiri. Intercellular mechanotransduction during multicellular morphodynamics. J. R. Soc. Interface 7:S341–S350, 2010.CrossRefGoogle Scholar
  15. 15.
    Kloth, L. C. Electrical stimulation for wound healing: a review of evidence from in vitro studies, animal experiments, and clinical trials. Int. J. Low. Extrem. Wounds 4:23–44, 2005.CrossRefGoogle Scholar
  16. 16.
    Kushiro, K., and A. R. Asthagiri. Modular design of micropattern geometry achieves combinatorial enhancements in cell motility. Langmuir 28:4357–4362, 2012.CrossRefGoogle Scholar
  17. 17.
    Lamalice, L., F. Le Boeuf, and J. Huot. Endothelial cell migration during angiogenesis. Circ. Res. 100:782–794, 2007.CrossRefGoogle Scholar
  18. 18.
    Lehmann, K., A. Rickenbacher, J.-H. Jang, C. E. Oberkofler, R. Vonlanthen, L. von Boehmer, B. Humar, R. Graf, P. Gertsch, and P.-A. Clavien. New insight into hyperthermic intraperitoneal chemotherapy: induction of oxidative stress dramatically enhanced tumor killing in in vitro and in vivo models. Ann. Surg. 256:730–737; discussion 737–738, 2012.Google Scholar
  19. 19.
    Li, L., R. Hartley, B. Reiss, Y. Sun, J. Pu, D. Wu, F. Lin, T. Hoang, S. Yamada, J. Jiang, and M. Zhao. E-cadherin plays an essential role in collective directional migration of large epithelial sheets. Cell. Mol. Life Sci. 69:2779–2789, 2012.CrossRefGoogle Scholar
  20. 20.
    Lin, F., F. Baldessari, T. Gyenge, C. Crenguta Sato, R. D. Chambers, J. G. Santiago, and E. C. Butcher, Lymphocyte electrotaxis in vitro and in vivo. J. Immunol. 181:2465–2471, 2008.Google Scholar
  21. 21.
    Long, H., G. Yang, and Z. Wang. Galvanotactic migration of EA.Hy926 endothelial cells in a novel designed electric field bioreactor. Cell Biochem. Biophys. 61:481–491, 2011.Google Scholar
  22. 22.
    Merks, R. M. H., E. D. Perryn, A. Shirinifard, and J. A. Glazier. Contact-inhibited chemotaxis in de novo and sprouting blood-vessel growth. PLoS Comput. Biol. 4:e1000163, 2008.CrossRefMathSciNetGoogle Scholar
  23. 23.
    Mycielska, M. E., and M. B. A. Djamgoz. Cellular mechanisms of direct-current electric field effects: galvanotaxis and metastatic disease. J. Cell Sci. 117:1631–1639, 2004.CrossRefGoogle Scholar
  24. 24.
    Ng, M. R., A. Besser, G. Danuser, and J. S. Brugge. Substrate stiffness regulates cadherin-dependent collective migration through myosin-II contractility. J. Cell Biol. 199:545–563, 2012.CrossRefGoogle Scholar
  25. 25.
    Patel, N., and M.-M. Poo. Orientation of neurite growth by extracellular electric fields. J. Neurosci. 2:483–496, 1982.Google Scholar
  26. 26.
    Pu, J., C. D. McCaig, L. Cao, Z. Zhao, J. E. Segall, and M. Zhao. EGF receptor signalling is essential for electric-field-directed migration of breast cancer cells. J. Cell Sci. 120:3395–3403, 2007.CrossRefGoogle Scholar
  27. 27.
    Pu, J., and M. Zhao. Golgi polarization in a strong electric field. J. Cell Sci. 118:1117–1128, 2005.CrossRefGoogle Scholar
  28. 28.
    Riahi, R., Y. Yang, D. D. Zhang, and P. K. Wong. Advances in wound-healing assays for probing collective cell migration. J. Lab. Autom. 17:59–65, 2012.CrossRefGoogle Scholar
  29. 29.
    Rodriguez, L., and I. Schneider. Directed cell migration in multi-cue environments. Integr. Biol. 5:1306–1323, 2013.CrossRefGoogle Scholar
  30. 30.
    Shapiro, S. A review of oscillating field stimulation to treat human spinal cord injury. World Neurosurg. 81:830–835, 2012.CrossRefGoogle Scholar
  31. 31.
    Song, B., Y. Gu, J. Pu, B. Reid, Z. Zhao, and M. Zhao. Application of direct current electric fields to cells and tissues in vitro and modulation of wound electric field in vivo. Nat. Protoc. 2:1479–1489, 2007.CrossRefGoogle Scholar
  32. 32.
    Sun, Y.-S., S.-W. Peng, K.-H. Lin, and J.-Y. Cheng. Electrotaxis of lung cancer cells in ordered three-dimensional scaffolds. Biomicrofluidics 6:014102-1–014102-14, 2012.Google Scholar
  33. 33.
    Sung, B. H., X. Zhu, I. Kaverina, and A. M. Weaver. Cortactin controls cell motility and lamellipodial dynamics by regulating ECM secretion. Curr. Biol. 21:1460–1469, 2011.CrossRefGoogle Scholar
  34. 34.
    Tao, Y., and M. Wang. Global solution for a chemotactic–haptotactic model of cancer invasion. Nonlinearity 21:2221–2238, 2008.CrossRefzbMATHMathSciNetGoogle Scholar
  35. 35.
    Tsai, H.-F., S.-W. Peng, C.-Y. Wu, H.-F. Chang, and J.-Y. Cheng. Electrotaxis of oral squamous cell carcinoma cells in a multiple-electric-field chip with uniform flow field. Biomicrofluidics 6:034116-1–034116-12, 2012.Google Scholar
  36. 36.
    van der Meer, A. D., K. Vermeul, A. A. Poot, J. Feijen, and I. Vermes. A microfluidic wound-healing assay for quantifying endothelial cell migration. Am. J. Physiol. Heart Circ. Physiol. 298:H719–H725, 2010.CrossRefGoogle Scholar
  37. 37.
    Vedula, S. R. K., M. C. Leong, T. L. Lai, P. Hersen, A. J. Kabla, C. T. Lim, and B. Ladoux. Emerging modes of collective cell migration induced by geometrical constraints. Proc. Natl. Acad. Sci. U.S.A. 109:12974–12979, 2012.CrossRefGoogle Scholar
  38. 38.
    Wang, S.-J., W. Saadi, F. Lin, C. M. Nguyen, and N. L. Jeon. Differential effects of EGF gradient profiles on MDA-MB-231 breast cancer cell chemotaxis. Exp. Cell Res. 300:180–189, 2004.CrossRefGoogle Scholar
  39. 39.
    Wang, E., M. Zhao, J. V. Forrester, and C. D. MCCaig. Re-orientation and faster, directed migration of lens epithelial cells in a physiological electric field. Exp. Eye Res. 71:91–98, 2000.CrossRefGoogle Scholar
  40. 40.
    Zhao, M., B. Song, J. Pu, T. Wada, B. Reid, G. Tai, F. Wang, A. Guo, P. Walczysko, Y. Gu, T. Sasaki, A. Suzuki, J. V. Forrester, H. R. Bourne, P. N. Devreotes, C. D. McCaig, and J. M. Penninger. Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. Nature 442:457–460, 2006.Google Scholar
  41. 41.
    Zhao, M. Electrical fields in wound healing-An overriding signal that directs cell migration. Semin. Cell Dev. Biol. 20:674–682, 2009.CrossRefGoogle Scholar

Copyright information

© Biomedical Engineering Society 2015

Authors and Affiliations

  1. 1.Department of Chemical EngineeringNortheastern UniversityBostonUSA
  2. 2.Department of BioengineeringNortheastern UniversityBostonUSA

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