Department of Physics and Astronomy, University College London, London, United Kingdom.
London Centre for Nanotechnology, University College London, London, United Kingdom.
Elife. 2021 May 20;10:e61011. doi: 10.7554/eLife.61011.
How cells with different genetic makeups compete in tissues is an outstanding question in developmental biology and cancer research. Studies in recent years have revealed that cell competition can either be driven by short-range biochemical signalling or by long-range mechanical stresses in the tissue. To date, cell competition has generally been characterised at the population scale, leaving the single-cell-level mechanisms of competition elusive. Here, we use high time-resolution experimental data to construct a multi-scale agent-based model for epithelial cell competition and use it to gain a conceptual understanding of the cellular factors that governs competition in cell populations within tissues. We find that a key determinant of mechanical competition is the difference in homeostatic density between winners and losers, while differences in growth rates and tissue organisation do not affect competition end result. In contrast, the outcome and kinetics of biochemical competition is strongly influenced by local tissue organisation. Indeed, when loser cells are homogenously mixed with winners at the onset of competition, they are eradicated; however, when they are spatially separated, winner and loser cells coexist for long times. These findings suggest distinct biophysical origins for mechanical and biochemical modes of cell competition.
不同遗传背景的细胞如何在组织中竞争是发育生物学和癌症研究中的一个突出问题。近年来的研究表明，细胞竞争既可以由短程生化信号驱动，也可以由组织中的远程机械应力驱动。迄今为止，细胞竞争通常在群体尺度上进行表征，竞争的单细胞水平机制仍难以捉摸。在这里，我们使用高时间分辨率的实验数据构建了一个上皮细胞竞争的多尺度基于代理的模型，并利用它来获得一个概念性的理解，即在组织内的细胞群体中，控制竞争的细胞因素。我们发现，机械竞争的一个关键决定因素是胜利者和失败者之间的稳态密度差异，而生长速率和组织组织的差异并不影响竞争的最终结果。相比之下，生化竞争的结果和动力学受到局部组织组织的强烈影响。事实上，当失败者细胞在竞争开始时与胜利者细胞均匀混合时，它们被消除；然而，当它们在空间上分离时，胜利者和失败者细胞可以长时间共存。这些发现表明，细胞竞争的机械和生化模式具有不同的生物物理起源。
