Day Nathan J, Michalowska Jasmine, Kelkar Manasi, Vallardi Giulia, Charras Guillaume, Lowe Alan R
Institute for the Physics of Living Systems, University College London, London, United Kingdom WC1E 6BT.
Institute for Structural and Molecular Biology, University College London, London, United Kingdom WC1E 6BT.
Mol Biol Cell. 2025 May 1;36(5):ar61. doi: 10.1091/mbc.E24-10-0481. Epub 2025 Mar 26.
Cell competition is often categorized into mechanical competition, during which loser cell elimination is induced by long-range mechanical effects, and biochemical competition, during which loser cell elimination results from direct cell-cell contacts. Before confluence, proliferation of winner cells has often been hypothesized to govern competition. Conversely, elimination of loser cells is thought to induce cell proliferation in its vicinity. However, causality is challenging to establish. To address this, we compute spatiotemporal signatures of competitive interactions using K-function clustering analysis. For this, we acquire long-term time lapses of two examples of mechanical (Scr) and biochemical (Ras) competition. We then segment cells, track them, and detect mitoses as well as eliminations. Finally, we perform K-function clustering to highlight spatiotemporal regions in which wild-type cell proliferation is enhanced or repressed around an elimination event. Our analysis reveals striking differences between the two types of competition. In the Scr competition, elimination seems driven by diffuse proliferation that does not cluster near the immediate elimination site. In contrast, Ras cell elimination is preceded by clustered proliferation of wild-type cells in the vicinity of the eventual Ras extrusion. Following loser elimination, an increase in local wild-type cell proliferation is observed in both competitions, although the timing and duration of these responses vary. This study not only sheds light on the diverse mechanisms of cell competition but also underscores the complexity of cellular interactions in tissue dynamics, providing new perspectives on cellular quality control and a new quantitative approach to characterize these interactions.
细胞竞争通常分为机械性竞争和生化性竞争，在机械性竞争中，失败者细胞的清除是由远距离机械效应诱导的，而在生化性竞争中，失败者细胞的清除是由直接的细胞间接触导致的。在汇合之前，通常假设获胜细胞的增殖主导竞争。相反，失败者细胞的清除被认为会诱导其附近的细胞增殖。然而，因果关系很难确立。为了解决这个问题，我们使用K函数聚类分析来计算竞争相互作用的时空特征。为此，我们获取了机械性竞争（Scr）和生化性竞争（Ras）两个例子的长期时间推移图像。然后我们对细胞进行分割、跟踪，并检测有丝分裂以及清除情况。最后，我们进行K函数聚类，以突出显示在清除事件周围野生型细胞增殖增强或受到抑制的时空区域。我们的分析揭示了两种竞争类型之间的显著差异。在Scr竞争中，清除似乎是由分散的增殖驱动的，这种增殖不会聚集在直接清除位点附近。相比之下，在最终的Ras挤出附近，野生型细胞的聚集增殖先于Ras细胞的清除。在失败者细胞被清除后，在两种竞争中都观察到局部野生型细胞增殖增加，尽管这些反应的时间和持续时间有所不同。这项研究不仅揭示了细胞竞争的多种机制，还强调了组织动态中细胞相互作用的复杂性，为细胞质量控制提供了新的视角，并提供了一种新的定量方法来表征这些相互作用。
