Intercellular forces driving stratification in a two-layer corneal epithelium: Insight from a Voronoi cell-based simulation model

The cornea is a self-renewing, multilayered tissue maintained with remarkable precision. Its outermost layer, the corneal epithelium, consists of five to seven stratified cell layers, sustained by two coordinated processes: the centripetal migration of transit amplifying cells (TACs) from peripheral limbal epithelial stem cells (LESCs), and delamination (vertical movement) of cells between layers. Despite this well-organized renewal, the mechanisms governing epithelial stratification remain largely unknown.

In this study, we present a two-dimensional Voronoi cell-based model that captures the dynamics of epithelial stratification. Our model incorporates two distinct epithelial layers—the basal and the suprabasal layers—and accounts for key cellular processes. These processes are mediated by mechanical interactions such as cell-substrate adhesion, as well as horizontal and vertical intercellular forces.

Our simulations show that cell delamination, which drives stratification, is strongly linked to TAC proliferation. In contrast, LESC division remains largely unchanged, suggesting that TACs buffer LESC activity, consistent with the slow-cycling nature of stem cells. This reveals that processes weakening the cell-to-substrate interaction will enhance the turnover of epithelial cells without the need for external growth factor induction, which is a notable finding. Interestingly, although increased shedding promotes division and delamination, excessive shedding leads to mechanical compensation via cell stretching in the upper layers. This mechanical response explains the presence of enlarged cells in the superficial layers of the corneal epithelium. Our model reveals a direct link between the shedding rate and the centripetal velocity of clonal growth, predicting that increased surface cell loss accelerates cell movement-a response similar to wound healing, where cells rapidly migrate to restore the damaged area.

These results highlight how cell size, migration, and turnover are tightly coupled, and offer deeper insights into how physical forces work together to maintain and rapidly restore epithelial integrity.

Author summary

The cornea is the eye’s clear outer layer, helping to protect the eye and focus light for sharp vision. Its outermost surface is made up of several layers of cells that are constantly renewed to keep the tissue healthy. This renewal happens through two main processes: new cells are produced by stem cells on the edge of the cornea and move inward, while older cells gradually move upward through the layers and eventually shed from the surface. However, the exact way these movements and layers are controlled is still not fully understood. In this study, we developed a computer model to explore how these cells grow, move, and replace one another over time. The model includes the physical forces, such as how strongly cells stick to each other and to the surface beneath them. Our results show that the upward movement of cells plays an important role in how often cells divide. We also found that when surface cells are lost more quickly such as in injury the cells below respond by dividing and moving faster to repair the surface. This helps us better understand how the cornea repairs itself and maintains its protective surface.