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

Abstract

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.T he morphogenesis of animal tissues results from coordinated changes in the shape, size, and packing of their constituent cells (1-3). These include autonomous cell shape changes (4), the response of cells to extrinsic stresses, and the effects of passive tissue deformation (5). When coordinated across a tissue, these active cellular processes and passive responses enable epithelial sheets to undergo shape changes while retaining relatively normal cell packing (6) and help return tissues to their resting state following a perturbation (7). Although the molecular basis of this cooperation is not understood, several studies have suggested a role for mechanical feedback (8, 9). Cell division has been suggested to participate in this feedback (10) because the rate of animal cell proliferation responds to changes in extrinsic forces in several experimental settings (9). Further, division makes an important contribution to tissue morphogenesis in animals (11, 12), accounts for much of the topological disorder observed in epithelia (13), can drive tissue elongation (10), and can facilitate the return to homeostatic cell packing following a deformation (2). Importantly, for each of these functions, the impact of cell division depends critically on the orientation of divisions.At the cellular level, relatively simple rules appear to govern division orientation. These rules were first explored by Hertwig (14), who showed that cells from early em...

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