The cornea: a clear case of a progenitor cell niche

The epithelial tissues that line our bodies are the frontline protection against the environment and microorganisms. Here, we have discovered how one of these tissues, the cornea, is maintained by a population of specialized progenitor cells located at the edge of the clear tissue.

HFSP Program Grant holder Guy Lyons and colleagues
authored on Tue, 03 February 2015

The epithelial cells that line the bodies of most vertebrates form a living barrier that protects them from damage by physical and biological sources, both external to the organisms and within cavities such as lungs and digestive tracts. Epithelial tissues also have specialized biological functions. They regulate the movement of molecules into and out of the body and give rise to appendages such as hair, nails, feathers and scales. These differentiated epithelial cells are constantly being lost by cell death or being shed and must be replaced. The rate of replenishment must be carefully regulated: too few replacement cells will cause the tissues to lose their integrity; too many will lead to a thickening of the tissue which impairs its biological roles and, in extreme cases, can lead to cancers. The source of the replacement cells is a population of epithelial progenitor cells. These are cells within the epithelium that lack many of its specialized functions, but are capable of perpetually giving rise to progeny, including both differentiated cells and more progenitor cells.

The HFSP project of Program Grant holders Guy Lyons, Silvio Gutkind and Mary Myerscough is using a lineage-tracing mouse model to identify epithelial clones within living tissues, primarily the tongue and skin, and to investigate how they interact with each other and evolve during carcinogenesis. Following an injection of tamoxifen, the epithelial progenitor cells start to make a randomly chosen combination of different colored fluorescent proteins, and continue to make that same color combination for the life of the animal. They confer this property on to their differentiated progeny, effectively "color-coding" different lineages, or clones, of epithelial cells. In the tongue and skin, the progenitor cells reside in the base of the epithelial layer, and their progeny migrate vertically towards the surface as they differentiate.

While the studies on tongue and skin were underway, it was noticed that the epithelial progenitor cells of the corneas of the mice also became labeled. This gave rise to the opportunity to follow the fate of individual corneal epithelial cell lineages over time in living animals. The cornea is a specialized epithelium that must maintain optical transparency and be continually replenished due to the loss of cells through physical abrasion by the blinking eyelid and damage by ultraviolet light. In collaboration with the lab of Nick Di Girolamo of the University of New South Wales, it was found that the progenitor cells labeled by the fluorescent proteins reside at the outer edge of the cornea in a region known as the limbus and that this population of cells is sufficient to maintain the integrity of the cornea. Progenitor cells located within the cornea proper, if they exist, are not needed, at least under homeostatic conditions. The location of the progenitor cells at the circumference of the cornea leads to a centripetal migration pattern, giving rise to a spoke-like appearance of lineage tracks, each composed of about 1,000 cells (see the multiple colored tracks of cells in the Figure; the blue, autofluorescent lens underlying them is also visible). This unexpected by-product of the project looking at tongue carcinogenesis has provided a powerful new model system for discovering the mechanisms underlying the regulation of the cornea during developmental and pathological conditions, and might be useful for developing transplantation therapies and artificial corneas for damaged eyes.

Reference

Tracing the fate of limbal epithelial progenitor cells in the murine cornea. Di Girolamo N, Bobba S, Raviraj V, Delic NC, Slapetova I, Nicovich PR, Halliday GM, Wakefield D, Whan R, Lyons JG. Stem Cells. 2015 Jan;33(1):157-69.

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