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Tissue size controls patterns of cell proliferation and migration in freely-expanding epithelia

Matthew A. Heinrich, Julienne M. LaChance, Tom J. Zajdel, Ricard Alert, Andrej Košmrlj, Daniel J. Cohen

Posted on: 21 May 2020

Preprint posted on 28 February 2020

Article now published in eLife at http://dx.doi.org/10.7554/eLife.58945

Size matters - epithelial tissue size dictates proliferation and migration dynamics

Selected by Ilaria Di Meglio

BACKGROUND

Cell proliferation and migration control represents a critical aspect of tissue formation and maintenance in vivo. However, the exact mechanisms by which tissues coordinate cellular behaviour to give rise to the complexity of a living organism are not fully understood. Among the first descriptions of tissue size control was the concept of contact inhibition, a term first proposed over half a century ago [1], which refers to the inhibition of cell migration and eventually proliferation [2] due to extensive mutual contact between cells as density in a tissue increases. Since then, many in vitro studies have employed model epithelial tissues to elucidate the underlying mechanisms that drive migration and proliferation control [3-8]. However, as remarked by Heinrich et al, most studies have restricted tissue growth to the sub-millimetric scale (<500 microns) and have not assessed long-term growth (more than 24 hours), which may give rise to emergent complexity of the tissue. With this in mind, the authors investigate how tissue size affects the spreading and growth of a model MDCK epithelium grown on patterns of >1mm in diameter.

 

KEY FINDINGS

A model epithelial tissue of MDCK cells is grown on circular patterns of either small (1.7mm) or large (3.4mm) diameter with the same starting cell density, and allowed to freely expand for over 46h (Fig.1). A first characterization of tissue dynamics indicates a difference in growth and migration dynamics between small and large tissues; relative area increase is greater for small tissues compared to large tissues, whereas tissue density increases monotonically in large tissues but not in small tissues. This difference is attributed to the finding that in the early stages of expansion of small tissues, migration plays a stronger role than cell division in small tissues. By relating the dynamics of area expansion to kinematic measurements, the authors find that the average radial expansion of the tissue depends on the perimeter-to-area ratio of the pattern and not on tissue size, which could explain why smaller patterns exhibit faster area expansion compared to larger patterns.

Figure 1 – Expansion dynamics of small (left) and large (right) millimetric-size cell monolayers over 46h of growth (taken from Fig. 1 in Heinrich et al., 2020)

 

Next, the authors characterize the migratory behaviour and find that migration dynamics at the outer edge are independent of tissue size; speed is high and constant in both small and large tissues. In contrast, migratory dynamics within the bulk of the tissue are size-dependent. Towards the inner region of tissues, the speed profile diverges, and small tissues exhibit a motile interior region while large tissues exhibit an interior region that is almost completely non-motile past 28h of growth. As opposed to speed, the radial component of the velocity field is almost identical for small and large tissues, decreasing as distance from the tissue edge increases. Interestingly, the difference between radial velocity and speed observed for small tissues is due to the emergence of tissue-spanning, fast vortices in the centre small tissues (Fig.2). The formation of these vortices coincides temporally and spatially with a local cell density minimum occurring in small tissues. Using a minimal model that recapitulates the cell density evolution in small and large tissues, the observed transient decrease in density at the centre of small tissues is attributed to the combination of outward tissue flow and exponential growth of the tissue.

Figure 2 – Cell trajectories for small (left) and large (right) tissues illustrate vortex formation in expanding epithelia (taken from Fig. 3 in Heinrich et al., 2020)

 

Finally, the authors also analyze the spatiotemporal cell cycle dynamics in small and large tissues by using MDCK cells expressing FUCCI, meaning that cells fluoresce in red (shown as magenta) during G1-phase and in green when in the S-G2-M phase of the cell cycle. Similar to migration dynamics, cell cycle dynamics are independent of tissue size in the outer region of tissues, where cells are in the S-G2-M phases and thus are actively cycling. In contrast, the inner regions of small and large tissues exhibit different dynamics; large tissues are populated primarily by (contact-inhibited) G1-phase cells, while small tissues exhibit a mix of both G1 and S-G2-M phase cells where local density minimum and vortices occur. The contact-inhibited state observed in the centre of large tissues actually propagates inwards and does not originate from the core of the tissue (Fig. 3).

Figure 3 – Fluorescence images at the end of the experiment (46h) of G1 phase (magenta) and G2 phase (green) cells shows spatial cell-cycle dynamics in small (left) and large (right) tissues (taken from Fig.5 in Heinrich et al., 2020)

 

Altogether, the authors show that tissue size dictates the migratory and proliferative behaviour of the tissue. Importantly, edge dynamics are conserved across tissue size whereas dynamics at the bulk of the tissue are not. In fact, while a small tissue eventually reaches the size of a large tissue, its internal dynamics are different from the large tissue at this size. Therefore, initial tissue size alters the growth constraints under which the tissue grows and this ultimately determines the growth patterns within the bulk of the tissue.

 

Why I like this preprint:

I found this preprint particularly interesting because it focuses on assessing the effect of tissue size and growth on the dynamics of both migration and proliferation. With a few exceptions, most studies using cultured MDCK cells focus on one of the two processes, yet the control and dynamics of both are equally important in the context of a growing tissue. Even more so, migration and proliferation patterns are highly interlinked, highlighting the importance of assessing both in a growing tissue. I think this study is also particularly relevant because it explores tissue dynamics at the larger scale, and indeed in vivo tissues can extend for millimeters or even meters! Finally, I liked the use of the FUCCI system in this study because it allows one to assess the effect of mechanics and in this case of tissue size on local cell cycle progression and not only on overall proliferation rate.

 

Questions to the authors:

  • The authors use plastic culture dishes in this study, which are several orders of magnitude stiffer than tissues. I think it would be interesting to assess the same dynamics at the millimetric-scale as has been done here but on substrates that are of physiologically relevant stiffness, which may give rise to further complexity in the dynamics observed.
  • Do you observe cell extrusion and if so is there a difference between small and large tissues, and between edge and tissue core?
  • The effect of aspect ratio on tissue expansion, which you assess by growing elliptical shaped tissues of major to minor axis ratios 8:1 or 4:1, also appears to impact vortex formation. The formation of a vortex is very evident in the movie S3 for the 8:1 tissue but not the 4:1 tissue – what could be the explanation for this difference?

References

  1. Abercrombie, M. and J.E. Heaysman, Observations on the social behaviour of cells in tissue culture. II. Monolayering of fibroblasts. Exp Cell Res, 1954. 6(2): p. 293-306.
  2. Stoker, M.G. and H. Rubin, Density dependent inhibition of cell growth in culture. Nature, 1967. 215(5097): p. 171-2.
  3. Nelson, C.M., et al., Emergent patterns of growth controlled by multicellular form and mechanics. Proc Natl Acad Sci U S A, 2005. 102(33): p. 11594-9.
  4. Puliafito, A., et al., Collective and single cell behavior in epithelial contact inhibition. Proc Natl Acad Sci U S A, 2012. 109(3): p. 739-44.
  5. Streichan, S.J., et al., Spatial constraints control cell proliferation in tissues. Proc Natl Acad Sci U S A, 2014. 111(15): p. 5586-91.
  6. Uroz, M., et al., Regulation of cell cycle progression by cell-cell and cell-matrix forces. Nat Cell Biol, 2018. 20(6): p. 646-654.
  7. Vedula, S.R., et al., Emerging modes of collective cell migration induced by geometrical constraints. Proc Natl Acad Sci U S A, 2012. 109(32): p. 12974-9.
  8. Wyatt, T.P., et al., Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis. Proc Natl Acad Sci U S A, 2015. 112(18): p. 5726-31

 

doi: https://doi.org/10.1242/prelights.20855

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