Reuse & Permissions

It is not necessary to obtain permission to reuse this article or its components as it is available under the terms of the Creative Commons Attribution 4.0 International license. This license permits unrestricted use, distribution, and reproduction in any medium, provided attribution to the author(s) and the published article's title, journal citation, and DOI are maintained. Please note that some figures may have been included with permission from other third parties. It is your responsibility to obtain the proper permission from the rights holder directly for these figures.

Export citation

Export citation

Choose format for download:

Download Citation
  • Open Access

Theory of cell size regulation underlying the onset of migration in adhered cells

Jonathan E. Ron1,2,* and Ram M. Adar1,†

  • *Contact author: jonathan.ron@weizmann.ac.il
  • †Contact author: radar@technion.ac.il

Phys. Rev. Research 8, 013058 – Published 20 January, 2026

DOI: https://doi.org/10.1103/1gkb-qs3z

Abstract

Cell migration is closely linked to cell shape, yet cell size is often assumed to remain constant. This assumption is challenged by recent experiments showing that cells undergo volume loss during spreading and swelling upon activation, with migration velocity correlated to cell size. In this work, we present a minimal theoretical framework for cellular size regulation and its influence on migration velocity. We connect cell size to membrane potential and active, actin-driven forces. Spatial inhomogeneities in these forces establish cell polarization and drive migration. Crucially, inhomogeneity is easier to establish over larger sizes, giving rise to a critical contact area, above which migration is possible. Our theory captures the coupled dynamics of cell volume, surface area, and motility and explains recent experiments on neutrophils.

View figure in article

Physics Subject Headings (PhySH)

Article Text

Supplemental Material

References (47)

  1. P. Friedl and D. Gilmour, Collective cell migration in morphogenesis, regeneration and cancer, Nat. Rev. Mol. Cell Biol. 10, 445 (2009).
  2. P. Friedl and S. Alexander, Cancer invasion and the microenvironment: Plasticity and reciprocity, Cell 147, 992 (2011).
  3. S. Nourshargh and R. Alon, Leukocyte migration into inflamed tissues, Immunity 41, 694 (2014).
  4. V. Hakim and P. Silberzan, Collective cell migration: A physics perspective, Rep. Prog. Phys. 80, 076601 (2017).
  5. J. E. Ron, P. Monzo, N. C. Gauthier, R. Voituriez, and N. S. Gov, One-dimensional cell motility patterns, Phys. Rev. Res. 2, 033237 (2020).
  6. J. E. Ron, M. Crestani, J. M. Kux, J. Liu, N. Al-Dam, P. Monzo, N. C. Gauthier, P. J. Sáez, and N. S. Gov, Emergent seesaw oscillations during cellular directional decision-making, Nat. Phys. 20, 501 (2024).
  7. J. Liu, J. Boix-Campos, J. E. Ron, J. M. Kux, N. S. Gov, and P. J. Sáez, Shape dynamics and migration of branched cells on complex networks, arXiv:2404.00118
  8. M. K. Driscoll, C. McCann, R. Kopace, T. Homan, J. T. Fourkas, C. Parent, and W. Losert, Cell shape dynamics: From waves to migration, PLoS Comput. Biol. 8, e1002392 (2012).
  9. C. Blanch-Mercader and J. Casademunt, Spontaneous motility of actin lamellar fragments, Phys. Rev. Lett. 110, 078102 (2013).
  10. D. L. Bodor, W. Pönisch, R. G. Endres, and E. K. Paluch, Of cell shapes and motion: The physical basis of animal cell migration, Dev. Cell 52, 550 (2020).
  11. I. Lavi, N. Meunier, R. Voituriez, and J. Casademunt, Motility and morphodynamics of confined cells, Phys. Rev. E 101, 022404 (2020).
  12. R. K. Sadhu, A. Iglič, and N. S. Gov, A minimal cell model for lamellipodia-based cellular dynamics and migration, J. Cell Sci. 136, jcs260744 (2023).
  13. A. C. Callan-Jones and R. Voituriez, Active gel model of amoeboid cell motility, New J. Phys. 15, 025022 (2013).
  14. C. Cadart, L. Venkova, P. Recho, M. C. Lagomarsino, and M. Piel, The physics of cell-size regulation across timescales, Nat. Phys. 15, 993 (2019).
  15. K. Xie, Y. Yang, and H. Jiang, Controlling cellular volume via mechanical and physical properties of substrate, Biophys. J. 114, 675 (2018).
  16. M. Guo, A. F. Pegoraro, A. Mao, E. H. Zhou, P. R. Arany, Y. Han, D. T. Burnette, M. H. Jensen, K. E. Kasza, J. R. Moore, F. C. Mackintosh, J. J. Fredberg, D. J. Mooney, J. Lippincott-Schwartz, and D. A. Weitz, Cell volume change through water efflux impacts cell stiffness and stem cell fate, Proc. Nat. Acad. Sci. USA 114, E8618 (2017).
  17. L. Venkova, A. S. Vishen, S. Lembo, N. Srivastava, B. Duchamp, A. Ruppel, A. Williart, S. Vassilopoulos, A. Deslys, J.-M. G. Arcos, et al., A mechano-osmotic feedback couples cell volume to the rate of cell deformation, eLife 11, e72381 (2022).
  18. R. M. Adar and S. A. Safran, Active volume regulation in adhered cells, Proc. Natl. Acad. Sci. USA 117, 5604 (2020).
  19. R. M. Adar, A. S. Vishen, J.-F. Joanny, P. Sens, and S. A. Safran, Volume regulation in adhered cells: Roles of surface tension and cell swelling, Biophys. J. 122, 506 (2023).
  20. E. Delpire and K. B. Gagnon, Water homeostasis and cell volume maintenance and regulation, Curr. Top. Membr. 81, 3 (2018).
  21. Q. Ni, Z. Ge, Y. Li, G. Shatkin, J. Fu, A. Sen, K. Bera, Y. Yang, Y. Wang, Y. Wu, et al., Cytoskeletal activation of NHE1 regulates mechanosensitive cell volume adaptation and proliferation, Cell Rep. 43, 114992 (2024).
  22. T. L. Nagy, E. Strickland, and O. D. Weiner, Neutrophils actively swell to potentiate rapid migration, Elife 12, RP90551 (2024).
  23. D. Tosteson and J. Hoffman, Regulation of cell volume by active cation transport in high and low potassium sheep red cells, J. Gen. Physiol. 44, 169 (1960).
  24. J. Keener and J. Sneyd, Mathematical Physiology: I: Cellular Physiology (Springer Science & Business Media, New York, 2010).
  25. A. R. Kay, How cells can control their size by pumping ions, Front. Cell Dev. Biol. 5, 41 (2017).
  26. See Supplemental Material at http://link.aps.org/supplemental/10.1103/1gkb-qs3z for the derivation of Eqs. (1), (2), and (13), and the details of the calculations presented in this article.
  27. R. M. Adar, Separation of ionic timescales explains dynamics of cellular volume regulation, Biophys. J. 124, 1944 (2025).
  28. R. Phillips, J. Kondev, and J. Theriot, Physical Biology of the Cell (Garland Science, New York, 2009).
  29. E. K. Hoffmann, I. H. Lambert, and S. F. Pedersen, Physiology of cell volume regulation in vertebrates, Physiol. Rev. 89, 193 (2009).
  30. N. C. Gauthier, M. A. Fardin, P. Roca-Cusachs, and M. P. Sheetz, Temporary increase in plasma membrane tension coordinates the activation of exocytosis and contraction during cell spreading, Proc. Natl. Acad. Sci. USA 108, 14467 (2011).
  31. G. Scita, S. Confalonieri, P. Lappalainen, and S. Suetsugu, IRSp53: Crossing the road of membrane and actin dynamics in the formation of membrane protrusions, Trends Cell Biol. 18, 52 (2008).
  32. A. Mukherjee, J. E. Ron, H. T. Hu, T. Nishimura, K. Hanawa-Suetsugu, B. Behkam, Y. Mimori‐Kiyosue, N. S. Gov, S. Suetsugu, and A. S. Nain, Actin filaments couple the protrusive tips to the nucleus through the I‐BAR domain protein IRSp53 for migration of elongated cells on 1D fibers, Adv. Sci. (Weinh) 10, 2207368 (2025).
  33. I. Dang, R. Gorelik, C. Sousa-Blin, E. Derivery, C. Guérin, J. Linkner, M. Nemethova, J. G. Dumortier, F. A. Giger, T. A. Chipysheva, et al., Inhibitory signalling to the Arp2/3 complex steers cell migration, Nature (London) 503, 281 (2013).
  34. P. Maiuri, J.-F. Rupprecht, S. Wieser, V. Ruprecht, O. Bénichou, N. Carpi, M. Coppey, S. De Beco, N. Gov, C.-P. Heisenberg, et al., Actin flows mediate a universal coupling between cell speed and cell persistence, Cell 161, 374 (2015).
  35. C. Yang, M. Pring, M. A. Wear, M. Huang, J. A. Cooper, T. M. Svitkina, and S. H. Zigmond, Mammalian CARMIL inhibits actin filament capping by capping protein, Dev. Cell 9, 209 (2005).
  36. M. Machacek, L. Hodgson, C. Welch, H. Elliott, O. Pertz, P. Nalbant, A. Abell, G. L. Johnson, K. M. Hahn, and G. Danuser, Coordination of Rho GTPase activities during cell protrusion, Nature (London) 461, 99 (2009).
  37. J. E. Ron, J. d'Alessandro, V. Cellerin, R. Voituriez, B. Ladoux, and N. S. Gov, Polarization and motility of one-dimensional multi-cellular trains, Biophys. J. 122, 4598 (2023).
  38. T. Bertrand, J. d'Alessandro, A. Maitra, S. Jain, B. Mercier, R.-M. Mège, B. Ladoux, and R. Voituriez, Clustering and ordering in cell assemblies with generic asymmetric aligning interactions, Phys. Rev. Res. 6, 023022 (2024).
  39. A. C. Callan-Jones and R. Voituriez, Actin flows in cell migration: From locomotion and polarity to trajectories, Curr. Opin. Cell Biol. 38, 12 (2016).
  40. R. J. Hawkins, R. Poincloux, O. Bénichou, M. Piel, P. Chavrier, and R. Voituriez, Spontaneous contractility-mediated cortical flow generates cell migration in three-dimensional environments, Biophys. J. 101, 1041 (2011).
  41. C. A. Wilson, M. A. Tsuchida, G. M. Allen, E. L. Barnhart, K. T. Applegate, P. T. Yam, L. Ji, K. Keren, G. Danuser, and J. A. Theriot, Myosin II contributes to cell-scale actin network treadmilling through network disassembly, Nature (London) 465, 373 (2010).
  42. C. Jurado, J. R. Haserick, and J. Lee, Slipping or gripping? Fluorescent speckle microscopy in fish keratocytes reveals two different mechanisms for generating a retrograde flow of actin, Mol. Biol. Cell 16, 507 (2005).
  43. M. Dembo and Y.-L. Wang, Stresses at the cell-to-substrate interface during locomotion of fibroblasts, Biophys. J. 76, 2307 (1999).
  44. Z. Messi, A. Bornert, F. Raynaud, and A. B. Verkhovsky, Traction forces control cell-edge dynamics and mediate distance sensitivity during cell polarization, Curr. Biol. 30, 1762 (2020).
  45. M. Lekka, K. Gnanachandran, A. Kubiak, T. Zieliński, and J. Zemła, Traction force microscopy—Measuring the forces exerted by cells, Micron 150, 103138 (2021).
  46. N. Ibata and E. M. Terentjev, Development of nascent focal adhesions in spreading cells, Biophys. J. 119, 2063 (2020).
  47. C. Cadart, E. Zlotek-Zlotkiewicz, L. Venkova, O. Thouvenin, V. Racine, M. L. Berre, S. Monnier, and M. Piel, Fluorescence exclusion measurement of volume in live cells, Methods Cell Biol. 139, 103 (2017).

Outline

Information

Sign In to Your Journals Account

Filter

Filter

Article Lookup

Enter a citation