In the epidermis of skin, a fine balance exists between proliferating progenitor cells and terminally differentiating cells. We examined the effects of TGF-/3s and retinoic acid (RA) on controlling this balance in normal human epidermal keratinocytes cultured under conditions where most morphological and biochemical features of epidermis in vivo are retained. Our results revealed marked and pleiotropic effects of both TGF-f3 and RA on keratinocytes. In contrast to retinoids, TGF-/3s acted on mitotically active basal cells to retard cell proliferation. Although withdrawal from the cell cycle is a necessary prerequisite for commitment to terminal differentiation, TGFf3s inhibited normal keratinization in suprabasal cells and promoted the type of differentiation commonly associated with wound-healing and epidermal hyperproliferation. The actions of TGF-,8s and RA on normal keratinization were synergistic, whereas those on abnormal differentiation associated with hyperproliferation were antagonistic. Under the conditions used here, the action of TGF-f3s on human keratinocytes was dominant over RA, and TGF-f3s did not seem to be induced as a consequence of RA treatment. Collectively, some TGF-f3-mediated effects on keratinizing cells can be uncoupled ´from the proliferative state of the basal keratinocyte.
Human keratinocytes, cultured on plastic and treated with TGF a, exhibit an increase in proliferation at the colony periphery, apparently as a consequence of enhanced cell migration. In this experiment, we investigate the possible role of TGF a on cell migration within a stratified squamous epithelium and examine the molecular basis underlying this phenomenon, using human epidermal raft cultures. Basal cells showed a marked increase in proliferation and migration. The organization of cells within the artificial tissue changed and island of basal cells entered the collagen matrix. Biochemical analysis of the response revealed a temporal induction in type 1 collagenase and gelatinase production, peaking within 12 hours after TGF a treatment. In contrast, cell migration seemed to be optimal at ---48 hours after TGF a treatment, suggesting that collagenase and gelatinase production may be a prerequisite to migration. Therefore TGF a might be involved in the epidermal cell migration and tissue remodelling.
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