The molecular mechanism of betacellulin induced corneal epithelial wound healing

Abstract

The epidermal growth factor receptor (EGFR) has been shown to be necessary and sufficient for mediating corneal epithelial homeostasis and wound healing. Experimentally, activation of EGFR by epidermal growth factor (EGF), increases healing in a corneal wound; however, therapeutic use of EGF does not improve corneal healing in patients. This study looks at wound healing elicited by other EGFR ligands, specifically betacellulin (BTC). Using human telomerase‐immortalized corneal epithelial cells (hTCEpi) in an in vitro wound healing assay, BTC was shown to be more efficacious than EGF during wound closure. Since BTC can also stimulate ErbB4, an EGFR family member, the efficacy of BTC may be due to activation of this receptor population. However, mRNA and protein levels were assessed in both hTCEpi and primary human corneal epithelial cells and revealed the absence of ErbB4. Differences in ligand binding properties could also explain BTC efficacy. Using radiolabeled ligands to assess binding sites, ligand affinity, pH sensitivity and competition revealed differences between BTC and EGF in these areas. We conclude that the increased efficacy seen with BTC over EGF is not from stimulation of ErbB4 but is, at least in part, from differences in binding properties. Funding: NIH 1R01GM092874 and P20 RR 017703.