Corneal Epithelial Stem Cells: Deficiency and Regulation Genevieve A. Secker & Julie T. Daniels Published online: 12 July 2008 # Humana Press 2008 Abstract The corneal epithelium is continuously renewed by a population of stem cells that reside in the corneoscleral junction, otherwise known as the limbus. These limbal epithelial stem cells (LESC) are imperative for corneal maintenance with deficiencies leading to in-growth of conjunctival cells, neovascularisation of the corneal stroma and eventual corneal opacity and visual loss. One such disease that has traditionally been thought to be due to LESC deficiency is aniridia, a pan-ocular congenital eye disease due to mutations in the PAX6 gene. Corneal changes or aniridia related keratopathy (ARK) seen in aniridia are typical of LESC deficiency. However, the pathophysiology behind ARK is still ill defined, with current theories suggesting it may be caused by a deficiency in the stem cell niche and adjacent corneal stroma, with altered wound healing responses also playing a role (Ramaesh et al, International Journal of Biochemistry & Cell Biology 37:547–557, 2005) or abnormal epidermal differentiation of LESC (Li et al., The Journal of Pathology 214:9, 2008). PAX6 is considered the master control gene for the eye and is required for normal eye development with expression continuing in the adult cornea, thus inferring a role for corneal repair and regeneration (Sivak et al., Developments in Biologicals 222:41–54, 2000). Studies of models of Pax6 deficiency, such as the small eyed (sey) mouse, should help to reveal the intrinsic and extrinsic mechanisms involved in normal LESC function. Keywords Limbal epithelial stem cells . Limbus . Cornea . Aniridia . PAX6 Limbal Epithelial Stem Cells All self-renewing tissue must contain a stem cell pool, which provides an unlimited supply of proliferating cells. This is true for the corneal epithelium with a large body of research indicating these cells reside in the limbal basal region and are aptly named limbal epithelial stem cells (LESC; Fig. 1). LESC share a number of features with other adult somatic stem cells. These include having small cell size [1], the lack expression of differentiation markers, such as cytokeratin 3/12 [2, 3] and high nuclear to cytoplasmic ratio [7]. LESC are considered to be primitive cells as they are slow cycling and therefore label retaining under normal conditions but have the ability to be highly proliferative in response to injury [5–7]. Stem cells have the ability to divide asymmetrically to repopulate the stem cell pool. Barbaro et al., recently found expression of C/EBPδ in a subset of LESC both in vivo and in vitro, and have suggested it is involved in the regulation of self renewal and cell cycle length of LESC. Other pathways have been linked to stem cell renewal, such as Notch-1. Corneal specific inducible ablation of Notch1 demonstrated differ- entiation of LESC into hyperplastic, keratinised skin like epithelium [8]. Furthermore LESC express progenitor markers, including, p63 [9], ABCG2 [10] and more recently N-cadherin Evidence for the Location of LESC to the Limbus The first experimental evidence for the location of LESC to the limbus was the movement of pigment from the limbal region towards an epithelial defect in rabbit corneas following wounding [11]. Some years later Davanger and Evenson [12], observed a similar migration of pigment from limbus to central cornea and proposed that the Stem Cell Rev (2008) 4:159–168 DOI 10.1007/s12015-008-9029-x G. A. Secker (*) : J. T. Daniels Cells for Sight Transplantation and Research Programme, Ocular Repair and Regeneration Biology Unit, Division of Pathology, UCL Institute of Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK e-mail: g.secker@ucl.ac.uk