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

  1. Buzz Baumb,h,2,3
  1. aCenter for Mathematics, Physics, and Engineering in the Life Sciences and Experimental Biology,
  2. bMedical Research Council's Laboratory for Molecular Cell Biology,
  3. gDepartment of Cell and Developmental Biology, and
  4. hInstitute for the Physics of Living Systems, University College London, London WC1E 6BT, United Kingdom;
  5. cLondon Centre for Nanotechnology, University College London, London, WC1H 0AH, United Kingdom;
  6. dBioengineering, University of California, Berkeley, CA 94720;
  7. eDepartment of Engineering, University of Cambridge, Cambridge CB2 1PZ, United Kingdom; and
  8. fCentre de Recherche de Biochimie Macromoléculaire, 34293 Montpellier, France

  1. Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved March 31, 2015 (received for review November 3, 2014)

Significance

Animal cells undergo a remarkable series of shape changes as they pass through mitosis and divide. In an epithelial tissue, the impact of these morphogenetic processes depends strongly on the orientation of division. However, the cues orienting divisions remain poorly understood. Here, we combine live imaging and mechanical perturbations with computational modeling to investigate the effects of shape changes accompanying mitosis and division in stretched monolayers in the absence of neighbor exchange. We show that divisions orient with the long cell axis rather than with the stress direction, and show how oriented divisions contribute to the restoration of cell packing and stress relaxation. In doing so, we identify a clear role for oriented cell division in morphogenetically active tissues.

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.

Footnotes

  • ↵1A.R.H. and M.L. contributed equally to this work.

  • ↵2G.T.C. and B.B. contributed equally to this work.

  • ↵3To whom correspondence may be addressed. Email: g.charras{at}ucl.ac.uk or b.baum{at}ucl.ac.uk.

  • Author contributions: T.P.J.W., A.J.K., G.T.C., and B.B. designed research; T.P.J.W., A.R.H., Q.C., and J.B. performed research; T.P.J.W., M.L., Q.C., J.B., and A.D. analyzed data; and T.P.J.W., A.J.K., G.T.C., and B.B. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1420585112/-/DCSupplemental.

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