Abstract
The molecular mechanism underlying the promotion of wound healing by TGF-beta 1 is incompletely understood. We report that TGF-beta 1 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-beta 1: (a) strongly upregulates the expression of the fibronectin receptor alpha 5 beta 1, the vitronectin receptor alpha v beta 5, and the collagen receptor alpha 2 beta 1 by differentially modulating the synthesis of their alpha and beta subunits; (b) downregulates the multifunctional alpha 3 beta 1 heterodimer; (c) induces the de novo expression and surface exposure of the alpha v beta 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 beta 1 and beta 4 dimers; and (f) causes a pericellular redistribution of alpha v beta 5. These data suggest that alpha 5 beta 1, alpha v beta 6, and alpha v beta 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-beta 1 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-beta 1-dependent stimulation of epidermal wound healing associated with a growth inhibitory effect on epithelial cells.
Highlights
H UMAr~epidermis, the outermost layer of skin, is a stratified squamous epithelium mainly composed of a single cell type, the keratinocyte
Wound healing is a complex phenomenonthat occurs through a sequenceof controlled events including: (a) an inflammatory stage involving aggregation of platelets and recruitment of macrophages, fibroblasts, and lymphocytesat the injury stie; (b) the formation of a provisional extracellular matrix, mainly composed of fibrinogen, fibrin, collagens, fibronectin, tenascin, and vitronectin; (c) the recruitmentof epidermal stem cells at the injury boundary, as well as the formation of an epithelial tongue of migrating keratinocytes at the very edge of the wound; and (d) the local synthesis and secretion, operated by the cell types mentioned above, of a wide variety of growth factors and cytokines regulating the formation of the granulating tissue, the migration and proliferation of keratinocytes, and the final remodeling of the scar, through a
We have previously shown that normal human basal keratinocytes express ~6~4, a2/31, c~3/~1, and ~v/35 integrin receptors, exposed on discrete plasma membrane regions in a polarized fashion (De Luca et al, 1990b; Marchisio et al, 1991)
Summary
H UMAr~epidermis, the outermost layer of skin, is a stratified squamous epithelium mainly composed of a single cell type, the keratinocyte. The a6B4 heterodimer is sharply localized on the basal aspect of the basal cell, is a component of hemidesmosomes, and mediates keratinocyte adhesion to the basement membrane by binding to both laminin and kalinin (De Luca et al, 1990b; Stepp et al, 1990; Sonnenberg et al, 1991; Zambruno et al, 1991; Niessen et al, 1994; Rousselle and Aumailley, 1994); in vitro, this integrin maintains its polar distribution and is organized in typical patches showing a "leopard skin" pattern in which spots correspond to microfilament-free areas (Marchisio et al, 1991; 1993), as expected from its association with hemidesmosomes and intermediate filaments (Stepp et al, 1990; Sonnenberg et al, 1991; Jones et al, 1991). This system has many advantages, since keratinocytes form epithelial colonies and cohesive sheets closely resembling normal human epidermis and maintain the differentiation pattern of their in vivo counterpart, such as to be used for autologous and permanent grafting onto patients (Green et al, 1979; Green, 1980; Gallico et al, 1984; De Luca et al, 1988, 1989, 1990a; Romagnoli et al, 1990)
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