Why does epithelia display heterogeneity? Bridging physical and biological concepts

  • Medhavi VishwakarmaEmail author
  • Jacopo Di RussoEmail author
Letter to the Editor

Epithelial cells construct inner and outer linings of our organs and function as physical barriers, thus, protecting the underlying tissue from infections, dehydration, and also aiding in efficient absorption of nutrients and gases (Alberts 2008). Cells within the epithelia perform these tasks, being jammed at their place while also making sure that epithelial homeostasis is maintained, failing in which can be potentially fatal for the tissue (Macara et al. 2014). Interestingly, the same cells can unjam and flow almost like a fluid during physiological and pathological situations such as organ development, wound healing and cancer metastasis (Friedl and Gilmour 2009; Mongera et al. 2018; Park et al. 2016; Sadati et al. 2013; Scarpa and Mayor 2016). In such situations, cells, rather than moving individually, migrate as a group in various patterns (Haeger et al. 2015; Petitjean et al. 2010; Poujade et al. 2007; Rorth 2012; Tarle et al. 2015). Reductionist view holds that such...



We appreciate the support of the interdisciplinary centre for clinical research (IZKF) and the institute for molecular and cellular anatomy (MOCA) at RWTH Aachen, as well as the school of cellular and molecular medicine at the University of Bristol. M.V. and J.D.R. are guest scientists at the Max Planck Institute for Medical Research in Heidelberg, Germany. We thank Adam Breitscheidel for his support in the graphic design and Natalia Simon for proofreading.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Alberts B (2008) Molecular biology of the cell. Reference edition, 5th edn. Garland Science, New YorkGoogle Scholar
  2. Al-Hussaini H, Kilarkaje N, Shahabi G, Al-Mulla F (2016) Proliferation and migration of peripheral retinal pigment epithelial cells are associated with the upregulation of wingless-related integration and bone morphogenetic protein signaling in Dark Agouti rats. Med Princ Pract 25:408–416. CrossRefGoogle Scholar
  3. Angelini TE, Hannezo E, Trepat X, Fredberg JJ, Weitz DA (2010) Cell migration driven by cooperative substrate deformation patterns. Phys Rev Lett 104:168104. CrossRefGoogle Scholar
  4. Angelini TE, Hannezo E, Trepat X, Marquez M, Fredberg JJ, Weitz DA (2011) Glass-like dynamics of collective cell migration. Proc Natl Acad Sci U S A 108:4714–4719. CrossRefGoogle Scholar
  5. Beck CR, Garcia-Perez J, Badge RM, Moran JV (2011) LINE-1 elements in structural variation and disease. Annu Rev Genomics Hum Genet 12:187–215. CrossRefGoogle Scholar
  6. Christ B, Poelmann RE, Mentink MMT, Groot G-dAC (1990) Vascular endothelial cells migrate centripetally within embryonic arteries. Anat Embryol 181:333–339. CrossRefGoogle Scholar
  7. Coleman HR, Chan C-C, Ferris FL, Chew EY (2008) Age-related macular degeneration. Lancet 372:1835–1845. CrossRefGoogle Scholar
  8. Das T, Safferling K, Rausch S, Grabe N, Boehm H, Spatz JP (2015) A molecular mechanotransduction pathway regulates collective migration of epithelial cells. Nat Cell Biol 17:276–287. CrossRefGoogle Scholar
  9. De S (2011) Somatic mosaicism in healthy human tissues. Trends Genet 27:217–223. CrossRefGoogle Scholar
  10. Debenedetti PG, Stillinger FH (2001) Supercooled liquids and the glass transition. Nature 410:259–267. CrossRefGoogle Scholar
  11. DeWard AD, Cramer J, Lagasse E (2014) Cellular heterogeneity in the mouse esophagus implicates the presence of a nonquiescent epithelial stem cell Population. Cell Rep 9:701–711. CrossRefGoogle Scholar
  12. Di Russo J et al (2017) Vascular laminins in physiology and pathology. Matrix Biol 57-58:140–148. CrossRefGoogle Scholar
  13. Edwards CM, Schwarz US (2011) Force localization in contracting cell layers. Phys Rev Lett 107:128101. CrossRefGoogle Scholar
  14. Fadul J, Rosenblatt J (2018) The forces and fates of extruding cells. Curr Opin Cell Biol 54:66–71. CrossRefGoogle Scholar
  15. Frank JA, Matthay MA (2003) Science review: mechanisms of ventilator-induced injury. Crit Care (London, England) 7:233–241. CrossRefGoogle Scholar
  16. Friedl P, Gilmour D (2009) Collective cell migration in morphogenesis, regeneration and cancer. Nat Rev Mol Cell Biol 10:445–457. CrossRefGoogle Scholar
  17. Garcia S, Hannezo E, Elgeti J, Joanny JF, Silberzan P, Gov NS (2015) Physics of active jamming during collective cellular motion in a monolayer. Proc Natl Acad Sci U S A 112:15314–15319. CrossRefGoogle Scholar
  18. Gardner RL (1986) Cell mingling during mammalian embryogenesis. J Cell Sci Suppl 4:337–356CrossRefGoogle Scholar
  19. Garrahan JP (2011) Dynamic heterogeneity comes to life. Proc Natl Acad Sci 108:4701–4702. CrossRefGoogle Scholar
  20. Gudipaty SA, Conner CM, Rosenblatt J, Montell DJ (2018) Unconventional ways to live and die: cell death and survival in development, homeostasis, and disease. Annu Rev Cell Dev Biol 34:311–332. CrossRefGoogle Scholar
  21. Haeger A, Wolf K, Zegers MM, Friedl P (2015) Collective cell migration: guidance principles and hierarchies. Trends Cell Biol 25:556–566. CrossRefGoogle Scholar
  22. Henkes S, Fily Y, Marchetti MC (2011) Active jamming: self-propelled soft particles at high density. Phys Rev E Stat Nonlinear Soft Matter Phys 84:040301. CrossRefGoogle Scholar
  23. Kajita M, Fujita Y (2015) EDAC: epithelial defence against cancer-cell competition between normal and transformed epithelial cells in mammals. J Biochem 158:15–23. CrossRefGoogle Scholar
  24. Keller R (2012) Developmental biology) Physical biology returns to morphogenesis. Science 338:201–203. CrossRefGoogle Scholar
  25. Khalilgharibi N et al. (2019) Stress relaxation in epithelial monolayers is controlled by the actomyosin cortex. Nat Phys 1–9.
  26. Ladoux B, Mège R-MM (2017) Mechanobiology of collective cell behaviours. Nat Rev Mol Cell Biol 18:743–757. CrossRefGoogle Scholar
  27. Macara IG, Guyer R, Richardson G, Huo Y, Ahmed SM (2014) Epithelial homeostasis. Curr Biol 24:R815–R825. CrossRefGoogle Scholar
  28. Malinverno C et al (2017) Endocytic reawakening of motility in jammed epithelia. Nat Mater 16:587–596. CrossRefGoogle Scholar
  29. Mark S, Shlomovitz R, Gov NS, Poujade M, Grasland-Mongrain E, Silberzan P (2010) Physical model of the dynamic instability in an expanding cell culture. Biophys J 98:361–370. CrossRefGoogle Scholar
  30. Mattsson J, Wyss HM, Fernandez-Nieves A, Miyazaki K, Hu Z, Reichman DR, Weitz DA (2009) Soft colloids make strong glasses. Nature 462:83–86. CrossRefGoogle Scholar
  31. Mayer C et al (2008) Asymmetric caging in soft colloidal mixtures. Nat Mater 7:780–784. CrossRefGoogle Scholar
  32. Mehes E, Vicsek T (2014) Collective motion of cells: from experiments to models. Integr Biol (Camb) 6:831–854. CrossRefGoogle Scholar
  33. Merkel M, Manning ML (2017) Using cell deformation and motion to predict forces and collective behavior in morphogenesis. Semin Cell Dev Biol 67:161–169. CrossRefGoogle Scholar
  34. Mobasseri SA, Zijl S, Salameti V, Walko G, Stannard A, Garcia-Manyes S, Watt FM (2019) Patterning of human epidermal stem cells on undulating elastomer substrates reflects differences in cell stiffness. Acta Biomater 87:256–264. CrossRefGoogle Scholar
  35. Mongera A et al (2018) A fluid-to-solid jamming transition underlies vertebrate body axis elongation. Nature 561:401–405. CrossRefGoogle Scholar
  36. Nagel AJLSR (1998) Jamming is not just cool any more. Nature 396Google Scholar
  37. Park JA, Fredberg JJ (2016) Cell jamming in the airway epithelium. Ann Am Thorac Soc 13(Suppl 1):S64–S67. Google Scholar
  38. Park JA et al (2015) Unjamming and cell shape in the asthmatic airway epithelium. Nat Mater 14:1040−+. CrossRefGoogle Scholar
  39. Park JA, Atia L, Mitchel JA, Fredberg JJ, Butler JP (2016) Collective migration and cell jamming in asthma, cancer and development. J Cell Sci.
  40. Pegoraro AF, Fredberg JJ, Park JA (2016) Problems in biology with many scales of length: cell-cell adhesion and cell jamming in collective cellular migration. Exp Cell Res 343:54–59. CrossRefGoogle Scholar
  41. Petitjean L, Reffay M, Grasland-Mongrain E, Poujade M, Ladoux B, Buguin A, Silberzan P (2010) Velocity fields in a collectively migrating epithelium. Biophys J 98:1790–1800. CrossRefGoogle Scholar
  42. Poujade M et al (2007) Collective migration of an epithelial monolayer in response to a model wound. Proc Natl Acad Sci U S A 104:15988–15993. CrossRefGoogle Scholar
  43. Rakyan VK, Blewitt ME, Druker R, Preis JI, Whitelaw E (2002) Metastable epialleles in mammals. Trends Genet 18:348–351CrossRefGoogle Scholar
  44. Rawles ME (1947) Origin of pigment cells from the neural crest in the mouse embryo. Physiol Zool 20:248–266CrossRefGoogle Scholar
  45. Rorth P (2012) Fellow travellers: emergent properties of collective cell migration. EMBO Rep 13:984–991. CrossRefGoogle Scholar
  46. Sabass B, Gardel ML, Waterman CM, Schwarz US (2008) High resolution traction force microscopy based on experimental and computational advances. Biophys J 94:207–220. CrossRefGoogle Scholar
  47. Sadati M, Taheri Qazvini N, Krishnan R, Park CY, Fredberg JJ (2013) Collective migration and cell jamming. Differentiation 86:121–125. CrossRefGoogle Scholar
  48. Sadati M, Nourhani A, Fredberg JJ, Taheri Qazvini N (2014) Glass-like dynamics in the cell and in cellular collectives. Wiley Interdiscip Rev Syst Biol Med 6:137–149. CrossRefGoogle Scholar
  49. Saw TB et al (2017) Topological defects in epithelia govern cell death and extrusion. Nature 544:212–216. CrossRefGoogle Scholar
  50. Scarpa E, Mayor R (2016) Collective cell migration in development. J Cell Biol 212:143–155. CrossRefGoogle Scholar
  51. Schwarz US, Soine JR (2015) Traction force microscopy on soft elastic substrates: A guide to recent computational advances. Biochim Biophys Acta 1853:3095–3104. CrossRefGoogle Scholar
  52. Sepulveda N, Petitjean L, Cochet O, Grasland-Mongrain E, Silberzan P, Hakim V (2013) Collective cell motion in an epithelial sheet can be quantitatively described by a stochastic interacting particle model. PLoS Comput Biol 9:e1002944. CrossRefGoogle Scholar
  53. Sixt M, Engelhardt B, Pausch F, Hallmann R, Wendler O, Sorokin LM (2001) Endothelial cell laminin isoforms, laminins 8 and 10, play decisive roles in T cell recruitment across the blood-brain barrier in experimental autoimmune encephalomyelitis. J Cell Biol 153:933–946. CrossRefGoogle Scholar
  54. Song J et al (2017) Endothelial basement membrane laminin 511 contributes to endothelial junctional tightness and thereby inhibits leukocyte transmigration. Cell Rep 18:1256–1269. CrossRefGoogle Scholar
  55. Steinberg MS (2007) Differential adhesion in morphogenesis: a modern view. Curr Opin Genet Dev 17:281–286. CrossRefGoogle Scholar
  56. Sunyer R et al (2016) Collective cell durotaxis emerges from long-range intercellular force transmission. Science 353:1157–1161. CrossRefGoogle Scholar
  57. Sutherland HG, Kearns M, Morgan HD, Headley AP, Morris C, Martin DI, Whitelaw E (2000) Reactivation of heritably silenced gene expression in mice. Mamm Genome 11:347–355CrossRefGoogle Scholar
  58. Tambe DT et al (2011) Collective cell guidance by cooperative intercellular forces. Nat Mater 10:469–475. CrossRefGoogle Scholar
  59. Tarle V, Ravasio A, Hakim V, Gov NS (2015) Modeling the finger instability in an expanding cell monolayer. Integr Biol (Camb) 7:1218–1227. CrossRefGoogle Scholar
  60. Trappe V, Prasad V, Cipelletti L, Segre PN, Weitz DA (2001) Jamming phase diagram for attractive particles. Nature 411:772–775. CrossRefGoogle Scholar
  61. Trepat X, Fredberg JJ (2011) Plithotaxis and emergent dynamics in collective cellular migration. Trends Cell Biol 21:638–646. CrossRefGoogle Scholar
  62. Trepat X, Sahai E (2018) Mesoscale physical principles of collective cell organization. Nat Phys 14:671–682. CrossRefGoogle Scholar
  63. Trepat X, Wasserman MR, Angelini TE, Millet E, Weitz DA, Butler JP, Fredberg JJ (2009) Physical forces during collective cell migration. Nat Phys 5:426–430. CrossRefGoogle Scholar
  64. Vishwakarma M, Di Russo J, Probst D, Schwarz US, Das T, Spatz JP (2018) Mechanical interactions among followers determine the emergence of leaders in migrating epithelial cell collectives. Nat Commun 9:3469. CrossRefGoogle Scholar
  65. Wagstaff L, Kolahgar G, Piddini E (2013) Competitive cell interactions in cancer: a cellular tug of war. Trends Cell Biol 23:160–167. CrossRefGoogle Scholar

Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.School of Cellular and Molecular MedicineUniversity Walk, University of BristolBristolUK
  2. 2.Max Planck Institute for Medical ResearchHeidelbergGermany
  3. 3.Interdisciplinary Centre for Clinical ResearchRWTH Aachen UniversityAachenGermany

Personalised recommendations