The Role of Cellular Replicative Lifespan and Stem Cell Dynamics on Corneal Epithelium Homeostasis and Pattern Formation

Abstract

The anterior outer transparent part of the eye, the cornea, acts as a lens that focuses light into the eye. In addition, it serves as a barrier that protects the eye against external hazards and injury and thus maintaining its integrity and its continuous regeneration is crucial for proper vision in vertebrates. Stem cells reside in niches at the circumference of the cornea, the limbus, which separates the cornea from the conjunctiva replenish and maintain corneal homeostasis. Recent lineage tracing experiments resulted in spike-like patterns that extended from the limbus to the center of the cornea over time. The mechanism that underlies these centripetal dynamics is not fully understood. We developed a novel mathematical model that capture the stochastic dynamics of epithelial cells and pattern formation in the cornea. Our model capture both short and long interaction range between cells. Moreover, we take into account two opposing models of stem cell dynamics that have been proposed: The Hierarchical model where stem-cells are rare long-lived, slow-dividing cells and the Stochastic model where stem-cells are abundant equipotent cells that divide frequently and their loss is dictated by neutral drift. We show that the replicative life-span of the cells and the spatial correlation between replication and removal from the cornea play a major role in whether homeostasis can be maintained without symmetry breaking signals. We derive the conditions that allow homeostasis that is consistent with biological timescales and mutants dynamics. We show how the conditions for self-organizing homeostasis depend on the stem cell dynamics and provide an experimental prediction to discriminate between the models. The result of this study can be extended to any cellular system in which spatial homeostasis is maintained through cell division.