Xue Shi-Lei, Yang Qiutan, Liberali Prisca, Hannezo Edouard
Department of Materials Science and Engineering, School of Engineering, Westlake University, Hangzhou, China.
Institute of Science and Technology Austria, Klosterneuburg, Austria.
Nat Phys. 2025;21(4):608-617. doi: 10.1038/s41567-025-02792-1. Epub 2025 Feb 28.
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.
胚胎发生过程中可重复的模式和形态生成仍未得到充分理解。肠道类器官形态发生涉及许多机械化学调节因子，如细胞类型特异性的细胞骨架力和渗透驱动的管腔体积变化。目前尚不清楚这些力如何在时间和空间上协调，以确保稳健的形态发生。在这里，我们展示了在类器官形态发生的最小模型中，对细胞骨架张力的机械敏感反馈如何产生形态双稳态。在该模型中，管腔体积变化可通过直接机械机制和间接机械敏感机制影响上皮形状。我们发现凸起和出芽的隐窝状态都是可能的，并且取决于体积变化的历史。我们通过生物物理和药理学实验测试了关键的建模假设，以证明双稳态如何解释实验观察结果，如管腔收缩时间的重要性以及最终形态发生状态对机械扰动的稳健性。这表明细胞张力和流体压力之间的反馈产生的双稳态可能是一种协调发育系统中多细胞形状变化的普遍机制。
