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Mol Biol Cell. 2017 Nov 7;28(23):3215-3228. doi: 10.1091/mbc.E17-06-0368. Epub 2017 Sep 20.

Local cellular neighborhood controls proliferation in cell competition.

Author information

1
London Centre for Nanotechnology, University College London, London WC1H 0AH, United Kingdom.
2
Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom.
3
Department of Physics and Astronomy, University College London, London WC1E 6BT, United Kingdom.
4
Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo, Hokkaido 060-0815, Japan.
5
Department of Physics and Astronomy, University College London, London WC1E 6BT, United Kingdom shiladitya.banerjee@ucl.ac.uk g.charras@ucl.ac.uk a.lowe@ucl.ac.uk.
6
Institute for the Physics of Living Systems, University College London, London WC1E 6BT, United Kingdom.
7
London Centre for Nanotechnology, University College London, London WC1H 0AH, United Kingdom shiladitya.banerjee@ucl.ac.uk g.charras@ucl.ac.uk a.lowe@ucl.ac.uk.
8
Institute for Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.

Abstract

Cell competition is a quality-control mechanism through which tissues eliminate unfit cells. Cell competition can result from short-range biochemical inductions or long-range mechanical cues. However, little is known about how cell-scale interactions give rise to population shifts in tissues, due to the lack of experimental and computational tools to efficiently characterize interactions at the single-cell level. Here, we address these challenges by combining long-term automated microscopy with deep-learning image analysis to decipher how single-cell behavior determines tissue makeup during competition. Using our high-throughput analysis pipeline, we show that competitive interactions between MDCK wild-type cells and cells depleted of the polarity protein scribble are governed by differential sensitivity to local density and the cell type of each cell's neighbors. We find that local density has a dramatic effect on the rate of division and apoptosis under competitive conditions. Strikingly, our analysis reveals that proliferation of the winner cells is up-regulated in neighborhoods mostly populated by loser cells. These data suggest that tissue-scale population shifts are strongly affected by cellular-scale tissue organization. We present a quantitative mathematical model that demonstrates the effect of neighbor cell-type dependence of apoptosis and division in determining the fitness of competing cell lines.

PMID:
28931601
PMCID:
PMC5687024
DOI:
10.1091/mbc.E17-06-0368
[Indexed for MEDLINE]
Free PMC Article

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