Defining compartmentalized stem cell populations with distinct cell division dynamics in the ocular surface epithelium

Abstract

Adult tissues contain label-retaining cells (LRCs) which are relatively slow-cycling and considered to represent a property of tissue stem cells (SCs). In the ocular surface epithelium, LRCs are present in the limbus and conjunctival fornix; however, the character of these LRCs remains unclear due to lack of appropriate molecular markers. Using three CreER transgenic mouse lines, we demonstrate that the ocular surface epithelium accommodates spatially-distinct populations with different cell division dynamics. In the limbus, long-lived Slc1a3CreER-labeled SCs either migrate centripetally toward the central cornea or slowly expand their clones laterally within the limbal region. In the central cornea, non-LRCs labeled with Dlx1CreER and K14CreER behave as short-lived progenitor cells. The conjunctival epithelium in the bulbar, fornix, and palpebral compartment is regenerated by regionally-unique SC populations. Severe damage to the cornea leads to the cancellation of SC compartments and conjunctivalization, whereas milder limbal injury induces a rapid increase of laterally-expanding clones in the limbus. Taken together, our work defines compartmentalized, multiple SC/progenitor populations of the mouse eye in homeostasis and their behavioral changes in response to injury.