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.

The extracellular matrix fibulin 7 maintains epidermal stem cell heterogeneity during skin aging

“…Slow‐cycling SCs express Dlx1 , while fast‐cycling SCs express Slc1a3 . Similar SCs heterogeneity and compartmentalization have also been described in the human skin (Ghuwalewala et al , 2022) and the eye epithelium (Ishii et al , 2020; Altshuler et al , 2021; Farrelly et al , 2021). Slow‐ and fast‐cycling SCs undergo distinct differentiation programs to give rise to the keratin (K)10+ interscale and K31+ scale structures of the tail skin, respectively (Gomez et al , 2013; Sada et al , 2016).…”

Discrete limbal epithelial stem cell populations mediate corneal homeostasis and wound healing

“…The transparent cornea is unique in the sense that epithelial cells are exposed to harmful conditions that include sun irradiation, toxicants, injuries, and infections (Secker and Daniels, 2008). The clarity and high accessibility of the cornea, however, allow robust SC lineage tracing (Amitai- Lange et al, 2015aLange et al, , 2015bDi Girolamo et al, 2015;Dora `et al, 2015) and SC depletion using simple vital microscopy (Nasser et al, 2018;Park et al, 2019;Ishii et al, 2020). Corneal epithelial SCs are known as rare slow-cycling cells that reside in the opaque limbus, a ring-shaped zone at the corneal-conjunctival boundary (Cotsarelis et al, 1989;Sartaj et al, 2017;Ebato et al, 1988;Pellegrini et al, 1999).…”

Dry eye disease in mice activates adaptive corneal epithelial regeneration distinct from constitutive renewal in homeostasis

“…Differentiating cells exit the cell cycle and migrate apically through the stratified corneal epithelium, which includes layers of suprabasal wing cells and the most superficial squamous cells. Recently, studies have demonstrated that there may be another noncanonical pathway of differentiation that gives rise to differentiated cells that extend circumferentially around the limbus ( 5 – 7 ).…”