The role of BCAM-positive cells in central cornea, limbus and conjunctiva

PROJECT SUMMARY/ABSTRACT A transparent cornea that maintains its architecture and refracts light is essential for visual acuity. Despite advances in corneal wound healing, individuals may develop blindness from scarring due to mechanical trauma, while others may experience a decline in the quality of light they perceive due to dry eye diseases, diabetic

keratopathy, and neurotrophic diseases. Improper healing after corneal injury can result in decreased visual acuity, photophobia, pain, tearing, and ulcerations. Severe, treatment-resistant corneal epithelial defects include persistent corneal epithelial defect, estimated to cause 100,000 cases/year in the US, and recurrent corneal

erosion, estimated to cause 4.23 cases/10,000 person-years. Novel treatments for corneal epithelial defects are urgently needed. The corneal epithelium is maintained by stem cells residing at the edge of the cornea in the limbus. These cells, known as limbal stem cells, give rise to basal epithelial progenitor cells, which migrate toward

the central cornea and play a role in differentiation and stratification of the corneal epithelium to support homeostasis. A recent mouse lineage tracing study demonstrated that basal epithelial cell migration from the limbus is the initial step in central corneal wound healing, indicating that abnormal basal cell migration likely

contributes to persistent corneal epithelial defects. In addition, studies have shown that disruption of extracellular matrix regulation, including the basement membrane, and focal adhesion molecules may be involved in recurrent corneal erosion. Thus, basal epithelial cells and their interaction with the surrounding microenvironment play an

important role in maintaining a healthy corneal epithelium. We suggest that a critical balance in the heterogeneity of basal epithelial cells is required to support homeostasis and wound healing. Our objective is to identify novel therapeutic targets for corneal epithelial defects by revealing the differential roles of basal epithelial cells in the

central cornea, limbus, and conjunctiva in corneal health and wound repair. We hypothesize that basal epithelial cells on the ocular surface have a specific molecular phenotype dependent on their location (central corneal, limbal, or conjunctival) and that the cells in each location differently contribute to homeostasis and wound healing

of the corneal epithelium. The proposed study will test this hypothesis by pursuing the following aims. In Aim 1, we will reveal the precise heterogeneity of ocular surface basal epithelial cells and the mechanism underlying the transition from a limbal to central corneal cell phenotype. In Aim 2, we will determine the functional roles of

genes expressed in basal epithelial cells in the central cornea. In Aim 3, we will determine the functional roles of genes expressed in basal epithelial cells in the limbus/conjunctiva. Our ultimate goal is to reveal the roles of each of the basal epithelial cell subpopulations during homeostasis and wound healing of the corneal epithelium,

and identify new candidate targets for the treatment of severe corneal epithelial defects.