Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: implications for wound healing.

Abstract

Abstract. The molecular mechanism underlying the promotion of wound healing by TGF-/31 is incompletely understood. We report that TGF-/5'I regulates the regenerative/migratory phenotype of normal human keratinocytes by modulating their integrin receptor repertoire. In growing keratinocyte colonies but not in fully stratified cultured epidermis, TGF-~I: (a) strongly upregulates the expression of the fibronectin receptor c~5~1, the vitronectin receptor t~v/~5, and the collagen receptor t~2/~l by differentially modulating the synthesis of their ot and/~ subunits; (b) downregulates the multifunctional oL3/~l heterodimer; (c) induces the de novo expression and surface exposure of the av#6 fibronectin receptor; (d) stimulates keratinocyte migration toward fibronectin and vitronectin; (e) induces a marked perturbation of the general mechanism of polarized domain sorting of both #1 and ~4 dimers; and (f) causes a pericellular redistribution of ~v/~5. These data suggest that ot5~l, ave6, and av/~5, not routinely used by keratinocytes resting on an intact basement membrane, act as "emergency" receptors, and uncover at least one of the molecular mechanisms responsible for the peculiar integrin expression in healing human wounds. Indeed, TGF-~I reproduces the integrin expression pattern of keratinocytes located at the injury site, particularly of cells in the migrating epithelial tongue at the leading edge of the wound. Since these keratinocytes are inhibited in their proliferative capacity, these data might account for the apparent paradox of a TGF-/5'l-dependent stimulation of epidermal wound healing associated with a growth inhibitory effect on epithelial cells. HUMAr~ epidermis, the outermost layer of skin, is a stratified squamous epithelium mainly composed of a single cell type, the keratinocyte. The epidermis survives through a self-renewal process (Green, 1980). Small progenitor keratinocytes (Barrandon and Green, 1987b), forming the innermost epidermal basal layer, regularly undergo mitosis, differentiation, and upward migration to replace terminally differentiated cornified cells that are continuously shed into the environment (Green, 1980;Watt, 1989;Fuchs, 1990). Basal epidermal keratinocytes rest on a basement membrane composed of a specific subset of extracellular matrix proteins such as laminin, type IV collagen, kalinin, nidogen, and heparan sulfate proteoglycan. The firm adhesion of basal keratinocytes, hence of the whole epidermis, to the basal lamina is mediated by hemidesmoAddress all correspondence to Dr. Michele De Luca, Unit of Epithelial Biology and Biotechnology, CBA, Centro di Biotecnologie Avanzate, Viale Benedetto XV no. 10, 16132, Genoa, Italy. Ph.: (39) (10) 5737423. Fax: (39) (10) 5737405.somes. These structures link the epithelial intermediate filament network to the dermal anchoring fibrils, which are mainly composed of type VII collagen and extend from the basement membrane to anchoring plaques in the papillary dermis (Jones et al., 1994). The keratinocyte behavior changes dramatically when ...

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