Advertisement

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

Abstract

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.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

References

  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.

  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.

  3. 3.

    Berens, P. J. CircStat: a MATLAB toolbox for circular statistics. Stat. Softw. 31:1–21, 2009.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  16. 16.

    Kushiro, K., and A. R. Asthagiri. Modular design of micropattern geometry achieves combinatorial enhancements in cell motility. Langmuir 28:4357–4362, 2012.

  17. 17.

    Lamalice, L., F. Le Boeuf, and J. Huot. Endothelial cell migration during angiogenesis. Circ. Res. 100:782–794, 2007.

  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.

  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.

  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.

  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.

  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.

  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.

  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.

  25. 25.

    Patel, N., and M.-M. Poo. Orientation of neurite growth by extracellular electric fields. J. Neurosci. 2:483–496, 1982.

  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.

  27. 27.

    Pu, J., and M. Zhao. Golgi polarization in a strong electric field. J. Cell Sci. 118:1117–1128, 2005.

  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.

  29. 29.

    Rodriguez, L., and I. Schneider. Directed cell migration in multi-cue environments. Integr. Biol. 5:1306–1323, 2013.

  30. 30.

    Shapiro, S. A review of oscillating field stimulation to treat human spinal cord injury. World Neurosurg. 81:830–835, 2012.

  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.

  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.

  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.

  34. 34.

    Tao, Y., and M. Wang. Global solution for a chemotactic–haptotactic model of cancer invasion. Nonlinearity 21:2221–2238, 2008.

  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.

  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.

  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.

  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.

  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.

  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.

  41. 41.

    Zhao, M. Electrical fields in wound healing-An overriding signal that directs cell migration. Semin. Cell Dev. Biol. 20:674–682, 2009.

Download references

Acknowledgments

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.

Author information

Correspondence to Anand R. Asthagiri.

Additional information

Associate Editor Jason M. Haugh oversaw the review of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 2 (AVI 170834 kb)

Supplementary material 3 (AVI 170834 kb)

Supplementary material 4 (AVI 166154 kb)

Supplementary material 5 (AVI 170834 kb)

Supplementary material 1 (PDF 684 kb)

Supplementary material 2 (AVI 170834 kb)

Supplementary material 3 (AVI 170834 kb)

Supplementary material 4 (AVI 166154 kb)

Supplementary material 5 (AVI 170834 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lalli, M.L., Asthagiri, A.R. Collective Migration Exhibits Greater Sensitivity But Slower Dynamics of Alignment to Applied Electric Fields. Cel. Mol. Bioeng. 8, 247–257 (2015). https://doi.org/10.1007/s12195-015-0383-x

Download citation

Keywords

  • Cell–cell interactions
  • Directional bias
  • Electrotaxis
  • Persistence