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 dur ing development. The mucous metaplasia produced by treating chick embr yo skin in organ culture with retinoic acid is a classical example of this property. It has been impossible so far to demonstrate that retin oids are able to provoke metaplasia of adult keratinocytes grown in vi tro, 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 pr evious work showed that adult human epidermal keratinocytes grown on d ermal equivalents at the surface of a culture medium containing physio logical amounts of retinoids form a normal keratinized epidermis, whil e when excess retinoic acid is added to the culture medium, keratiniza tion is prevented but stratification is not. Here we show that the dis tribution of tissue- and differentiation-stage-specific markers in ret inoic acid-treated epithelium is similar to that of the oral mucosa. M oreover, when the excess retinoic acid is removed, a new epithelium is formed beneath the ''old'' one and this epithelium displays an epider mal orthokeratinized phenotype, whereas the ''old'' epithelium remains unchanged. This phenomenon of ''partial reversibility'', as well as t he mutually exclusive distribution of the markers of the two alternati ve routes of differentiation, demonstrate that retinoic acid is indeed able to provoke metaplasia of adult epidermal keratinocytes.