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Surface-tension-induced budding drives alveologenesis in human mammary gland organoids


Organ development involves complex shape transformations driven by active mechanical stresses that sculpt the growing tissue1,2. Epithelial gland morphogenesis is a prominent example where cylindrical branches transform into spherical alveoli during growth3,4,5. Here we show that this shape transformation is induced by a local change from anisotropic to isotropic tension within the epithelial cell layer of developing human mammary gland organoids. By combining laser ablation with optical force inference and theoretical analysis, we demonstrate that circumferential tension increases at the expense of axial tension through a reorientation of cells that correlates with the onset of persistent collective rotation around the branch axis. This enables the tissue to locally control the onset of a generalized Rayleigh–Plateau instability, leading to spherical tissue buds6. The interplay between cell motion, cell orientation and tissue tension is a generic principle that may turn out to drive shape transformations in other cell tissues.

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Fig. 1: Morphology of human mammary gland organoids depends on the mechanical interaction with the ECM.
Fig. 2: Alveoli are under isotropic tension and cylindrical branches are under axially biased tension.
Fig. 3: Alveoli undergo collective rotation.
Fig. 4: A hydrodynamic model with anisotropic tension and ECM elasticity can explain the shape transition.

Data availability

Microscopy data that support the findings of this study are available in Zenodo at Source data are provided with this paper. All other relevant data supporting the key findings of this study are available within the article and Supplementary Information or from the corresponding authors upon reasonable request.

Code availability

The code used for analysing the data of this study is available in Zenodo at


  1. 1.

    Petridou, N. I., Grigolon, S., Salbreux, G., Hannezo, E. & Heisenberg, C.-P. Fluidization-mediated tissue spreading by mitotic cell rounding and non-canonical Wnt signalling. Nat. Cell Biol. 21, 169–178 (2019).

    Article  Google Scholar 

  2. 2.

    Karzbrun, E., Kshirsagar, A., Cohen, S. R., Hanna, J. H. & Reiner, O. Human brain organoids on a chip reveal the physics of folding. Nat. Phys. 14, 515–522 (2018).

    Article  Google Scholar 

  3. 3.

    Wang, S., Sekiguchi, R., Daley, W. P. & Yamada, K. M. Patterned cell and matrix dynamics in branching morphogenesis. J. Cell Biol. 216, 559–570 (2017).

    Article  Google Scholar 

  4. 4.

    Linnemann, J. R. et al. Quantification of regenerative potential in primary human mammary epithelial cells. Development 142, 3239–3251 (2015).

    Google Scholar 

  5. 5.

    Rios, A. C. et al. Intraclonal plasticity in mammary tumors revealed through large-scale single-cell resolution 3D imaging. Cancer Cell 35, 618–632.e6 (2019).

    Article  Google Scholar 

  6. 6.

    Rayleigh, L. On the instability of jets. Proc. Lond. Math. Soc. s1–10, 4–13 (1878).

    MathSciNet  Article  Google Scholar 

  7. 7.

    Inman, J. L., Robertson, C., Mott, J. D. & Bissell, M. J. Mammary gland development: cell fate specification, stem cells and the microenvironment. Development 142, 1028–1042 (2015).

    Article  Google Scholar 

  8. 8.

    Bar-Ziv, R., Tlusty, T., Moses, E., Safran, S. A. & Bershadsky, A. Pearling in cells: a clue to understanding cell shape. Proc. Natl Acad. Sci. USA 96, 10140–10145 (1999).

    ADS  Article  Google Scholar 

  9. 9.

    Bar-Ziv, R. & Moses, E. Instability and ‘pearling’ states produced in tubular membranes by competition of curvature and tension. Phys. Rev. Lett. 73, 1392–1395 (1994).

    ADS  Article  Google Scholar 

  10. 10.

    Dong, B., Hannezo, E. & Hayash, S. Balance between apical membrane growth and luminal matrix resistance determines epithelial tubule shape. Cell Rep. 7, 941–950 (2014).

    Article  Google Scholar 

  11. 11.

    Pérez-González, C. et al. Active wetting of epithelial tissues. Nat. Phys. 15, 79–88 (2019).

    Article  Google Scholar 

  12. 12.

    Tetley, R. J. et al. Tissue fluidity promotes epithelial wound healing. Nat. Phys. 15, 1195–1203 (2019).

    Article  Google Scholar 

  13. 13.

    He, B., Doubrovinski, K., Polyakov, O. & Wieschaus, E. Apical constriction drives tissue-scale hydrodynamic flow to mediate cell elongation. Nature 508, 392–396 (2014).

    ADS  Article  Google Scholar 

  14. 14.

    Maître, J.-L. et al. Adhesion functions in cell sorting by mechanically coupling the cortices of adhering cells. Science 338, 253–256 (2012).

    ADS  Article  Google Scholar 

  15. 15.

    Chatterjee, S. J., Halaoui, R., Deagle, R. C., Rejon, C. & McCaffrey, L. Numb regulates cell tension required for mammary duct elongation. Biol. Open 8, bio042341 (2019).

    Article  Google Scholar 

  16. 16.

    Parmar, H. & Cunha, G. R. Epithelial–stromal interactions in the mouse and human mammary gland in vivo. Endocr. Relat. Cancer 11, 437–458 (2004).

    Article  Google Scholar 

  17. 17.

    Buchmann, B. et al. Mechanical plasticity of collagen directs invasive branching morphogenesis in human mammary gland organoids. Nat. Commun. 12, 2759 (2021).

    ADS  Article  Google Scholar 

  18. 18.

    Alcaraz, J. et al. Collective epithelial cell invasion overcomes mechanical barriers of collagenous extracellular matrix by a narrow tube-like geometry and MMP14-dependent local softening. Integr. Biol. 3, 1153–1166 (2011).

    Article  Google Scholar 

  19. 19.

    Wisdom, K. M. et al. Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments. Nat. Commun. 9, 4144 (2018).

    ADS  Article  Google Scholar 

  20. 20.

    Hall, M. S. et al. Fibrous nonlinear elasticity enables positive mechanical feedback between cells and ECMs. Proc. Natl Acad. Sci. USA 113, 14043–14048 (2016).

    Article  Google Scholar 

  21. 21.

    Lecuit, T., Lenne, P.-F. & Munro, E. Force generation, transmission, and integration during cell and tissue morphogenesis. Annu. Rev. Cell Dev. Biol. 27, 157–184 (2011).

    Article  Google Scholar 

  22. 22.

    Brodland, G. W. et al. Video force microscopy reveals the mechanics of ventral furrow in vagination in Drosophila. Proc. Natl Acad. Sci. USA 107, 22111–22116 (2010).

    ADS  Article  Google Scholar 

  23. 23.

    Brodland, G. W. et al. CellFIT: a cellular force-inference toolkit using curvilinear cell boundaries. PLoS ONE 9, 1–15 (2014).

    Article  Google Scholar 

  24. 24.

    Kong, W. et al. Experimental validation of force inference in epithelia from cell to tissue scale. Sci. Rep. 9, 14647 (2019).

    ADS  Article  Google Scholar 

  25. 25.

    Bischofs, I. B. & Schwarz, U. S. Cell organization in soft media due to active mechanosensing. Proc. Natl Acad. Sci. USA 100, 9274–9279 (2003).

    ADS  Article  Google Scholar 

  26. 26.

    Tanner, K., Mori, H., Mroue, R., Bruni-Cardoso, A. & Bissell, M. J. Coherent angular motion in the establishment of multicellular architecture of glandular tissues. Proc. Natl Acad. Sci. USA 109, 1973–1978 (2012).

    ADS  Article  Google Scholar 

  27. 27.

    Thüroff, F., Goychuk, A., Reiter, M. & Frey, E. Bridging the gap between single-cell migration and collective dynamics. eLife 8, e46842 (2019).

    Article  Google Scholar 

  28. 28.

    Tambe, D. T. et al. Collective cell guidance by cooperative intercellular forces. Nat. Mater. 10, 469–475 (2011).

    ADS  Article  Google Scholar 

  29. 29.

    Jain, S. et al. The role of single-cell mechanical behaviour and polarity in driving collective cell migration. Nat. Phys. 16, 802–809 (2020).

    Article  Google Scholar 

  30. 30.

    Segerer, F. J., Thüroff, F., Alberola, A. P., Frey, E. & Rädler, J. O. Emergence and persistence of collective cell migration on small circular micropatterns. Phys. Rev. Lett. 114, 228102 (2015).

    ADS  Article  Google Scholar 

  31. 31.

    Tinevez, J.-Y. et al. Role of cortical tension in bleb growth. Proc. Natl Acad. Sci. USA 106, 18581–18586 (2009).

    ADS  Article  Google Scholar 

  32. 32.

    Villeneuve, C. et al. aPKCi triggers basal extrusion of luminal mammary epithelial cells by tuning contractility and vinculin localization at cell junctions. Proc. Natl Acad. Sci. USA 116, 24108–24114 (2019).

    Article  Google Scholar 

  33. 33.

    Colombelli, J., Grill, S. W. & Stelzer, E. H. K. Ultraviolet diffraction limited nanosurgery of live biological tissues. Rev. Sci. Instrum. 75, 472–478 (2004).

    ADS  Article  Google Scholar 

  34. 34.

    Edelstein, A. et al. Advanced methods of microscope control using μManager software. J. Biol. Methods 1, e10 (2014).

    Article  Google Scholar 

  35. 35.

    Bradski, G. The OpenCV library. Dr. Dobb’s J. Software Tools 25, 120–125 (2000).

    Google Scholar 

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We gratefully acknowledge financial support by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 810104-PoInt) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Project ID 201269156–SFB 1032. A.G. was supported by a DFG fellowship through the Graduate School of Quantitative Biosciences Munich (QBM). We thank C. Gabka from the Nymphenburg Clinic for Plastic and Aesthetic Surgery for providing the primary human mammary gland tissue. We thank L. Ushakov for his aid in implementing the force inference algorithm.

Author information




P.A.F., C.H.S. and A.R.B. designed the research. P.A.F., B.B, L.K.E. and M.K.R. performed the experiments and analysed the data. A.G., P.A.F. and E.F. performed theoretical interpretation of the experiments. P.A.F., A.G., E.F. and A.R.B. wrote the paper. A.R.B., E.F. and C.H.S. supervised the project. All the authors revised and edited the manuscript.

Corresponding authors

Correspondence to Christina H. Scheel, Erwin Frey or Andreas R. Bausch.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review informationNature Physics thanks Sanjay Kumar, Mingming Wu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–12, Table 1 and Discussion.

Reporting Summary

Supplementary Video 1

Cylindrical branches flow into the organoid body after hydrolysis of the collagen matrix.

Supplementary Video 2

Laser ablation of organoids for branches grown in the attached (left) and floating (right) configurations.

Supplementary Video 3

Laser ablation in the presence of cytochalasin D.

Supplementary Video 4

Representative examples of cell dynamics over one day. All organoids stem from the same donor (M25) and were grown in floating gels. Note that the branch shape strongly correlates with the type of motion: axial translation in cylindrical branches and rotation in nascent and mature alveoli.

Supplementary Video 5

Long-term observation of cell dynamics shows that alveologenesis and collective cell rotation are correlated (donor, M28).

Supplementary Video 6

Addition of HECD-1 antibody against E-cadherin abolishes alveolar rotation within 15–25 h (donor, M25).

Supplementary Video 7

Cell dynamics at ×25 magnification. This experiment corresponds to Supplementary Fig. 4a (donor, M25).

Supplementary Video 8

Cell dynamics at ×25 magnification. This experiment corresponds to Supplementary Fig. 4b (donor, M25).

Source data

Source Data Fig. 1

Statistical source data for Fig. 1.

Source Data Fig. 2

Statistical source data for Fig. 2.

Source Data Fig. 3

Statistical source data for Fig. 3.

Source Data SI

Source data for Supplementary Information.

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Fernández, P.A., Buchmann, B., Goychuk, A. et al. Surface-tension-induced budding drives alveologenesis in human mammary gland organoids. Nat. Phys. 17, 1130–1136 (2021).

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