Mechanochemical bistability of intestinal organoids enables robust morphogenesis

article Mechanochemical bistability of intestinal organoids enables robust morphogenesis published yes Shi-lei Xue author 31D2C804-F248-11E8-B48F-1D18A9856A87 Qiutan Yang author Prisca Liberali author Edouard B Hannezo author 3A9DB764-F248-11E8-B48F-1D18A9856A870000-0001-6005-1561 EdHa department Design Principles of Branching Morphogenesis project Active mechano-chemical description of the cell cytoskeleton project Reproducible pattern and form generation during embryogenesis is poorly understood. Intestinal organoid morphogenesis involves a number of mechanochemical regulators such as cell-type-specific cytoskeletal forces and osmotically driven lumen volume changes. It is unclear how these forces are coordinated in time and space to ensure robust morphogenesis. Here we show how mechanosensitive feedback on cytoskeletal tension gives rise to morphological bistability in a minimal model of organoid morphogenesis. In the model, lumen volume changes can impact the epithelial shape via both direct mechanical and indirect mechanosensitive mechanisms. We find that both bulged and budded crypt states are possible and dependent on the history of volume changes. We test key modelling assumptions via biophysical and pharmacological experiments to demonstrate how bistability can explain experimental observations, such as the importance of the timing of lumen shrinkage and robustness of the final morphogenetic state to mechanical perturbations. This suggests that bistability arising from feedback between cellular tensions and fluid pressure could be a general mechanism that coordinates multicellular shape changes in developing systems. https://research-explorer.ista.ac.at/download/19373/20129/2025_NaturePhysics_Xue.pdf application/pdfno Springer Nature2025 eng Nature Physics 1745-2473 1745-2481 2403.19900 40248571 00143407280000110.1038/s41567-025-02792-1 21 Xue, Shi-lei, Qiutan Yang, Prisca Liberali, and Edouard B Hannezo. “Mechanochemical Bistability of Intestinal Organoids Enables Robust Morphogenesis.” Nature Physics. Springer Nature, 2025. <a href="https://doi.org/10.1038/s41567-025-02792-1">https://doi.org/10.1038/s41567-025-02792-1</a>. Xue, S., Yang, Q., Liberali, P., & Hannezo, E. B. (2025). Mechanochemical bistability of intestinal organoids enables robust morphogenesis. Nature Physics. Springer Nature. <a href="https://doi.org/10.1038/s41567-025-02792-1">https://doi.org/10.1038/s41567-025-02792-1</a> S. Xue, Q. Yang, P. Liberali, E.B. Hannezo, Nature Physics 21 (2025). Xue S, Yang Q, Liberali P, Hannezo EB. 2025. Mechanochemical bistability of intestinal organoids enables robust morphogenesis. Nature Physics. 21, 078104. Xue S, Yang Q, Liberali P, Hannezo EB. Mechanochemical bistability of intestinal organoids enables robust morphogenesis. Nature Physics. 2025;21. doi:<a href="https://doi.org/10.1038/s41567-025-02792-1">10.1038/s41567-025-02792-1</a> Xue, Shi-lei, et al. “Mechanochemical Bistability of Intestinal Organoids Enables Robust Morphogenesis.” Nature Physics, vol. 21, 078104, Springer Nature, 2025, doi:<a href="https://doi.org/10.1038/s41567-025-02792-1">10.1038/s41567-025-02792-1</a>. S. Xue, Q. Yang, P. Liberali, and E. B. Hannezo, “Mechanochemical bistability of intestinal organoids enables robust morphogenesis,” Nature Physics, vol. 21. Springer Nature, 2025. 193732025-03-09T23:01:28Z2025-09-30T10:47:36Z