Stromal-Epithelial Interactions in the Cornea

Abstract

Communication between corneal epithelial cells and keratocytes is likely to contribute to normal maintenance, wound healing, corneal tissue organization, and the patho- physiology of corneal disease. Interactions between these cells are mediated via cytokines, growth factors, and their receptors. Other mechanisms of communication may also occur.

Hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) are classical paracrine mediators produced by the keratocytes that regulate the proliferation, motility, and differentiation of corneal epithelial cells via the HGF receptor and KGF receptor (stromal to epithelial interactions). HGF is also produced by the lacrimai gland and is a component in the tear film. After corneal wounding, however, HGF protein and HGF and KGF mRNA production is stimulated in keratocyte cells. Upregulation of HGF and KGF production in the keratocyte cells is likely mediated by the release of IL-1 from the injured epithelial cells. Thus, IL-1 serves as a molecular transducer that signals keratocytes that the epithelium has been injured and stimulates the stromal cells to increase production of HGF and KGF to modulate corneal epithelial wound healing.

Epithelial to stromal interactions are also important in the cornea. It has recently been demonstrated that the disappearance of anterior keratocytes following corneal epithelial injury is mediated via programmed cell death (apoptosis) characterized by chromatin condensation, nucleosomal fragmentation, the formation of apoptotic bodies, and DNA fragmentation. Our data suggest that IL-1, and possibly soluble Fas ligand, released from corneal epithelial cells by injury, trigger apoptosis in the keratocytes via IL-1 receptor and Fas, respectively, expressed by the stromal cells.

It is hypothesized this system is physiologically activated by infection of corneal epithelial cells by viral pathogens such as herpes simplex virus and that death of the anterior keratocytes functions to limit the extension of virus. Injury to the epithelium during refractive surgical procedures such as photorefractive keratectomy (PRK) could be perceived by the cornea as a massive viral infection of the epithelium that results in apoptosis of the anterior keratocytes. Keratocyte apoptosis may be the initiating event in the subsequent wound healing response and a promising site for interventions to control wound healing following refractive surgery. These observations provide a physiologic explanation for the difference that has been noted in wound healing response between surface ablation procedures (i.e., PRK) where the central corneal epithelium is injured and procedures such as LASIK in which the central corneal epithelium is maintained. This epithelial-stromal interactive system also provides a working hypothesis for the pathogenesis of ectatic diseases such as keratoconus where various abnormalities that might shift the balance between keratocyte proliferation and apoptosis could lead to a slow loss of the total number of keratocytes and, therefore, to stromal thinning.

Clinicians and scientists have long speculated regarding the importance of communications occurring between corneal epithelial and stromal cells (stromal-epithelial interactions) and the significance of these interactions in maintenance of normal corneal structure and function, pathophysiology of corneal disease, and corneal wound healing.¹ Over the past few years specific growth factor/cytokine-receptor systems have been detected in corneal cells in vivo and in vitro and some of their functions identified. This paper will review what is currently known about these corneal modulators of stromal-epithelial interactions and some of the processes they regulate.