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HGF, MAPK, and a Small Physiological Electric Field Interact during Corneal Epithelial Cell Migration

¹From the Department of Biomedical Sciences, Institute of Medical Sciences, and the ²Department of Ophthalmology, University of Aberdeen, Aberdeen, Scotland, United Kingdom.

PURPOSE. To investigate the effects of hepatocyte growth factor (HGF) and a small applied electric field (EF) on corneal epithelial cell (CEC) migration.

METHODS. Primary cultures of bovine CECs were exposed to an EF (25–250 mV/mm) in the presence or absence of HGF (100 ng/mL). The rate and directionality of CEC migration were quantified. The expression of HGF receptors (HGFRs), p42/44 mitogen-activated protein kinase (MAPK) and the time-course of activation of p42/44 MAPK were investigated by confocal microscopy and Western blot analysis.

RESULTS. CECs migrated significantly faster in the presence of an EF, HGF, or HGF and an EF combined. The distribution of HGFRs was intracellular and in the presence of an EF was concentrated in the cathode-facing side. This EF-induced asymmetrical accumulation of HGFRs correlated with the direction of CEC migration. The application of HGF or an EF led to the activation of the MAPK signaling pathway and in the presence of an EF, activation of MAPK was greater in the cathode-facing half of the CECs. Inhibition of the MAPK signaling pathway by PD98059 (100 µM) reduced the ability of HGF and an EF to enhance the rate of CEC migration, but did not alter EF-induced cathodal directionality.

CONCLUSIONS. These data suggest that both HGF and an EF augment the rate of CEC migration through activation of p42/44 MAPK. Moreover, EF-induced redistribution of HGFRs and asymmetry of MAPK signaling, although not instrumental in directing CEC migration cathodally, may be important for the signaling and maintenance of migration.

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