NEU DIFFERENTIATION FACTOR UP-REGULATES EPIDERMAL MIGRATION AND INTEGRIN EXPRESSION IN EXCISIONAL WOUNDS

Neu differentiation factor (NDF) is a 44-kD glycoprotein which was iso lated from ras-transformed rat fibroblasts and indirectly induces tyro sine phosphorylation of the HER-2/neu receptor via binding to either t he HER-3 or HER-4 receptor. NDF contains a receptor binding epidermal growth factor (EGF)-like domain and is a member of the EGF family. The re are multiple different isoforms of NDF which arise by alternative s plicing of a single gene. To date, in vivo biologic activities have no t been demonstrated for any NDF isoform. Since NDF, HER-2/neu, and HER -3 are present in skin, and other EGF family members can influence wou nd keratinocytes in vivo, we investigated whether NDF would stimulate epidermal migration and proliferation in a rabbit ear model of excisio nal wound repair. In this model, recombinant human NDF-alpha(2) (rhNDF -alpha(2)), applied once at the time of wounding, induced a highly sig nificant increase in both epidermal migration and epidermal thickness at doses ranging from 4 to 40 mu g/cm(2). In contrast, rhNDF-alpha(1), rhNDF-beta(1), and rhNDF-beta(2) had no apparent biologic effects in this model. rhNDF-alpha(2), also induced increased neoepidermal expres sion of alpha(5) and alpha(6) integrins, two of the earliest integrins to appear during epidermal migration. In addition, rhNDF-alpha(2)-tre ated wounds exhibited increased neoepidermal expression of cytokeratin 10 and filaggrin, both epidermal differentiation markers. NDF alpha i soforms were expressed in dermal fibroblasts of wounded and unwounded skin, while both HER-2/neu and HER-3 were expressed in unwounded epide rmis and dermal adnexa. In wounds, HER-2/neu expression was markedly d ecreased in the wound neoepidermis while neoepidermal HER-3 expression was markedly upregulated. Taken together, these results suggest that endogenous NDF-alpha(2), may function as a paracrine mediator directin g initial epidermal migration during cutaneous tissue repair.