Retinoic acid provokes metaplasia of epithelium formed in vitro by adult human epidermal keratinocytes.

A striking effect of retinoids is their ability to alter cell fate during development. The mucous metaplasia produced by treating chick embryo skin in organ culture with retinoic acid is a classical example of this property. It has been impossible so far to demonstrate that retinoids are able to provoke metaplasia of adult keratinocytes grown in vitro, although these agents have been shown to block terminal epidermal differentiation, to induce increased synthesis of mucopolysaccharides, and to induce the ectopic expression of K19 and K13 keratins. Our previous work showed that adult human epidermal keratinocytes grown on dermal equivalents at the surface of a culture medium containing physiological amounts of retinoids form a normal keratinized epidermis, while when excess retinoic acid is added to the culture medium, keratinization is prevented but stratification is not. Here we show that the distribution of tissue- and differentiation-stage-specific markers in retinoic acid-treated epithelium is similar to that of the oral mucosa. Moreover, when the excess retinoic acid is removed, a new epithelium is formed beneath the "old" one and this epithelium displays an epidermal orthokeratinized phenotype, whereas the "old" epithelium remains unchanged. This phenomenon of "partial reversibility", as well as the mutually exclusive distribution of the markers of the two alternative routes of differentiation, demonstrate that retinoic acid is indeed able to provoke metaplasia of adult epidermal keratinocytes.