On the origin of universal cell shape variability in a confluent epithelial monolayer

Cell shape is fundamental in biology. The average cell shape can influence crucial biological functions, such as cell fate and division orientation. But cell-to-cell shape variability is often regarded as noise. In contrast, recent works reveal that shape variability in diverse epithelial monolayers follows a nearly universal distribution. However, the origin and implications of this universality remain unclear. Here, assuming contractility and adhesion are crucial for cell shape, characterized via aspect ratio (r), we develop a mean-field analytical theory for shape variability. We find that all the system-specific details combine into a single parameter α that governs the probability distribution function (PDF) of r; this leads to a universal relation between the standard deviation and the average of r. The PDF for the scaled r is not strictly but nearly universal. In addition, we obtain the scaled area distribution, described by the parameter μ, α and μ together can distinguish the effects of changing physical conditions, such as maturation, on different system properties. We have verified the theory via simulations of two distinct models of epithelial monolayers and with existing experiments on diverse systems. We demonstrate that in a confluent monolayer, average shape determines both the shape variability and dynamics. Our results imply that cell shape distribution is inevitable, where a single parameter describes both statics and dynamics and provides a framework to analyze and compare diverse epithelial systems. In contrast to existing theories, our work shows that the universal properties are consequences of a mathematical property and should be valid in general, even in the fluid regime.