Neu differentiation factor upregulates epidermal migration and integrin expression in excisional wounds.

Abstract

Neu differentiation factor (NDF) is a 44-kD glycoprotein which was isolated from ras-transformed rat , applied once at the time of wounding, induced a highly significant increase in both epidermal migration and epidermal thickness at doses ranging from 4 to 40 ,ug/cm2. In contrast, rhNDF-al, rhNDF-pl, and rhNDF-132 had no apparent biologic effects in this model. rhNDF-a2 also induced increased neoepidermal expression of as and a6 integrins, two of the earliest integrins to appear during epidermal migration. In addition, rhNDF-a2-treated wounds exhibited increased neoepidermal expression of cytokeratin 10 and filaggrin, both epidermal differentiation markers. NDF a isoforms were expressed in dermal fibroblasts of wounded and unwounded skin, while both HER-2/neu and HER-3 were expressed in unwounded epidermis and dermal adnexa. In wounds, HER-2/neu expression was markedly decreased in the wound neoepidermis while neoepidermal HER-3 expression was markedly upregulated.

Neu differentiation factor/heregulin induction by hepatocyte and keratinocyte growth factors

“…EGF itself is less likely to be involved, as no signi®cant induction of EGF mRNA was observed in this model system (S Werner, unpublished observations). These data suggest that NDF mediates some of the proliferative and/or di erentiating e ects of KGF during skin wound repair, consistent with the prior reports that recombinant NDF stimulated re-epithelization and epidermal migration in excisional wounds (Danilenko et al, 1995).…”

Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation

“…Another di erentiation-like e ect of neuregulin, namely maturation of mammary cells into milk-producing cells, could be mimicked by anti-ErbB-4 antibodies , suggesting that this receptor plays a role in cell fate determination, rather than in promoting cell proliferation. Consistent with this notion, neuregulin-mediated proliferation of keratinocytes (Danilenko et al, 1995;Marikovsky et al, 1995), mammary cells (Holmes et al, 1992) and Schwann cells correlates with coexpression of ErbB-2 together with ErB-3, rather than with ErbB-4. Thus, ErbB-3 action may be restricted to cell proliferation, in agreement with the potent mitogenic activity of this receptor in normal (PinkasKramarski et al, 1996) and in tumor cells (Alimandi et al, 1995;Wallasch et al, 1995).…”

“…An example is provided by the mammary gland, where NDF acts as as inducer of di erentiation in vitro (Bacus et al, 1993) and a ects lobulo-alveolar budding and milk production in isolated glands (Yang et al, 1995). Likewise, di erent isoforms of NDF can extend cell survival or act as potent mitogens for cultured keratinocytes (Marikovsky et al, 1995), while a speci®c isoform mediates directional migration and epidermal differentiation during cutaneous wound repair in vivo (Danilenko et al, 1995).…”

EGF receptor signaling inhibits keratinocyte apoptosis: evidence for mediation by Bcl-XL

“…First, highly speci®c anti-EGFR monoclonal antibodies (mAb) abrogate proliferation and ligand-induced tyrosine phosphorylation of a 170 kDa ErbB-1-immunoreactive protein in normal human keratinocytes (Klein et al, 1992). Second, while NDF is expressed in the dermis in vivo, and in cultured keratinocytes in vitro, it is not mitogenic for keratinocytes in culture (Danilenko et al, 1995;Poumay and Pittelkow, 1995). Third, keratinocytes do not detectably express ErbB-4 (Marikovsky et al, 1995).…”