Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis.

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Wyatt, Tom PJ 
Harris, Andrew R 
Lam, Maxine 
Cheng, Qian 
Bellis, Julien 

Cell division plays an important role in animal tissue morphogenesis, which depends, critically, on the orientation of divisions. In isolated adherent cells, the orientation of mitotic spindles is sensitive to interphase cell shape and the direction of extrinsic mechanical forces. In epithelia, the relative importance of these two factors is challenging to assess. To do this, we used suspended monolayers devoid of ECM, where divisions become oriented following a stretch, allowing the regulation and function of epithelial division orientation in stress relaxation to be characterized. Using this system, we found that divisions align better with the long, interphase cell axis than with the monolayer stress axis. Nevertheless, because the application of stretch induces a global realignment of interphase long axes along the direction of extension, this is sufficient to bias the orientation of divisions in the direction of stretch. Each division redistributes the mother cell mass along the axis of division. Thus, the global bias in division orientation enables cells to act collectively to redistribute mass along the axis of stretch, helping to return the monolayer to its resting state. Further, this behavior could be quantitatively reproduced using a model designed to assess the impact of autonomous changes in mitotic cell mechanics within a stretched monolayer. In summary, the propensity of cells to divide along their long axis preserves epithelial homeostasis by facilitating both stress relaxation and isotropic growth without the need for cells to read or transduce mechanical signals.

cell division, mechanical feedback, mitotic rounding, morphogenesis, quantitative biology, Animals, Cadherins, Cell Division, Cell Shape, Dogs, Epithelial Cells, Epithelium, Green Fluorescent Proteins, Homeostasis, Madin Darby Canine Kidney Cells, Mitosis, Morphogenesis, Software, Stress, Mechanical
Journal Title
Proc Natl Acad Sci U S A
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Proceedings of the National Academy of Sciences
Biotechnology and Biological Sciences Research Council (BB/K013696/1)
We thank D. Farquharson and S. Townsend at the University College London workshop and Joel Jennings and Richard Adams for help with model development. B.B. and J.B. thank Cancer Research UK, the Biotechnology and Biological Sciences Research Council (BBSRC) (Grant BB/K009001), the French Institut National du Cancer, and Matthieu Piel for support. T.P.J.W. and A.D. were supported by the Engineering and Physical Sciences Research Council. A.R.H. was supported by the BBSRC (Grant BB/K013521 to G.C. and A.K.), and M.L. was supported by the Agency for Science Technology and Research (Singapore) and the Wellcome Trust.