Intestinal organoids derived from single cells undergo complex crypt–villus patterning and morphogenesis. However, the nature and coordination of the underlying forces remains poorly characterized. Here, using light-sheet microscopy and large-scale imaging quantification, we demonstrate that crypt formation coincides with a stark reduction in lumen volume. We develop a 3D biophysical model to computationally screen different mechanical scenarios of crypt morphogenesis. Combining this with live-imaging data and multiple mechanical perturbations, we show that actomyosin-driven crypt apical contraction and villus basal tension work synergistically with lumen volume reduction to drive crypt morphogenesis, and demonstrate the existence of a critical point in differential tensions above which crypt morphology becomes robust to volume changes. Finally, we identified a sodium/glucose cotransporter that is specific to differentiated enterocytes that modulates lumen volume reduction through cell swelling in the villus region. Together, our study uncovers the cellular basis of how cell fate modulates osmotic and actomyosin forces to coordinate robust morphogenesis.
Nature Cell Biology
We acknowledge the members of the Lennon-Duménil laboratory for sharing the mouse line of Myh9-GFP. We are grateful to the members of the Liberali laboratory and the FMI facilities for their support. We thank E. Tagliavini for IT support; L. Gelman for assistance and training; S. Bichet and A. Bogucki for helping with histology of mouse tissues; H. Kohler for fluorescence-activated cell sorting; G. Q. G. de Medeiros for maintenance of light-sheet microscopy; M. G. Stadler for scRNA-seq analysis; G. Gay for discussions on the 3D vertex model; the members of the Liberali laboratory, C. P. Heisenberg and C. Tsiairis for reading and providing feedback on the manuscript. Funding: Q.Y. is supported by a Postdoc fellowship from Peter und Taul Engelhorn Stiftung (PTES). This work received funding from the European Research Council (ERC) under the EU Horizon 2020 research and Innovation Programme Grant Agreement no. 758617 (to P.L.), the Swiss National Foundation (SNF) (POOP3_157531, to P.L.) and from the ERC under the EU Horizon 2020 Research and Innovation Program Grant Agreements 851288 (to E.H.) and the Austrian Science Fund (FWF) (P31639, to E.H.).
Yang Q, Xue S, Chan CJ, et al. Cell fate coordinates mechano-osmotic forces in intestinal crypt formation. Nature Cell Biology. 2021. doi:10.1038/s41556-021-00700-2
Yang, Q., Xue, S., Chan, C. J., Rempfler, M., Vischi, D., Maurer-Gutierrez, F., … Liberali, P. (2021). Cell fate coordinates mechano-osmotic forces in intestinal crypt formation. Nature Cell Biology. Springer Nature. https://doi.org/10.1038/s41556-021-00700-2
Yang, Qiutan, Shi-lei Xue, Chii Jou Chan, Markus Rempfler, Dario Vischi, Francisca Maurer-Gutierrez, Takashi Hiiragi, Edouard B Hannezo, and Prisca Liberali. “Cell Fate Coordinates Mechano-Osmotic Forces in Intestinal Crypt Formation.” Nature Cell Biology. Springer Nature, 2021. https://doi.org/10.1038/s41556-021-00700-2.
Q. Yang et al., “Cell fate coordinates mechano-osmotic forces in intestinal crypt formation,” Nature Cell Biology. Springer Nature, 2021.
Yang Q, Xue S, Chan CJ, Rempfler M, Vischi D, Maurer-Gutierrez F, Hiiragi T, Hannezo EB, Liberali P. 2021. Cell fate coordinates mechano-osmotic forces in intestinal crypt formation. Nature Cell Biology.
Yang, Qiutan, et al. “Cell Fate Coordinates Mechano-Osmotic Forces in Intestinal Crypt Formation.” Nature Cell Biology, Springer Nature, 2021, doi:10.1038/s41556-021-00700-2.