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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


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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

Authors and Affiliations



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.

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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.

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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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