DOTS: DNA origami tension sensors for studying T cell mechanobiology
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Coupling of cell shape, matrix and tissue dynamics ensures embryonic patterning robustness
Tissue patterning coordinates morphogenesis, cell dynamics and fate specification. Understanding how precision in patterning is robustly achieved despite inherent developmental variability during mammalian embryogenesis remains a challenge. Here, based on cell dynamics quantification and simulation, we show how salt-and-pepper epiblast and primitive endoderm (PrE) cells pattern the inner cell mass of mouse blastocysts. Coupling cell fate and dynamics, PrE cells form apical polarity-dependent actin protrusions required for RAC1-dependent migration towards the surface of the fluid cavity, where PrE cells are trapped due to decreased tension. Concomitantly, PrE cells deposit an extracellular matrix gradient, presumably breaking the tissue-level symmetry and collectively guiding their own migration. Tissue size perturbations of mouse embryos and their comparison with monkey and human blastocysts further demonstrate that the fixed proportion of PrE/epiblast cells is optimal with respect to embryo size and tissue geometry and, despite variability, ensures patterning robustness during early mammalian development.
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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.
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