Epithelium Stratifies via Nucleation and Growth Induced by Foam-Geometric Instability

The epithelium undergoes stratification, transitioning from a monolayer to a multilayer structure, across broad phenomena. Recent studies have identified several cell behaviors as triggers, including junctional tension, cell density and geometry, and topological defects. However, how these factors drive stratification throughout the entire epithelium remains poorly understood. Here, we report a mechanism underlying epithelial stratification that mirrors the physics of phase transition. Combining cell culture with three-dimensional vertex modeling, we demonstrate that epithelium stratifies via nucleation-growth process, i.e., multilayer origins dispersedly appear and expand across the epithelium via unordered intermediate states. This process is akin to a phase transition induced by a mechanical instability inherent in the foam-like geometry of the epithelium. Moreover, this concept applies to embryonic skin development and malignant transformation of cancer. These findings conceptualize epithelial stratification as a form of a phase transition governed by nucleation and growth, offering a physical perspective on various epithelial developments.