UNDIFFERENTIATED KERATINOCYTES CONTROL GROWTH, MORPHOLOGY, AND ANTIGEN EXPRESSION OF NORMAL MELANOCYTES THROUGH CELL-CELL CONTACT

BACKGROUND: Melanocytes in the normal human epidermis are generally de ndritic and neither proliferate nor express melanoma-associated antige ns. In culture, on the other hand, melanocytes are bi- to tripolar, pr oliferate with 2 to 4 day doubling times, and express melanoma-associa ted antigens. This observation prompted us to investigate the regulato ry role of keratinocytes for growth, morphology, and antigen expressio n of melanocytes. EXPERIMENTAL DESIGN: Melanocytes and keratinocytes w ere cultured under three different co-culture conditions: (a) separate d by a semiporous membrane, (b) in monolayer cultures allowing direct contact between cells, and (c) in three-dimensional epidermal reconstr ucts. RESULTS: Melanocytes separated from keratinocytes by semiporous membranes remained di- and tripolar and could not proliferate in mediu m optimal for keratinocytes. When cell-cell contact was established be tween melanocytes and undifferentiated, but not differentiated, kerati nocytes, melanocytes proliferated at a rate similar to keratinocytes a nd they developed multiple dendrites. In co-cultures allowing the mult i-layered growth of keratinocytes, melanocytes were nonproliferative w hen juxtaposed to undifferentiated keratinocytes in the basal layer, b ut proliferated when surrounded by differentiated keratinocytes in the intermediate and upper layers. Expression of melanoma-associated anti gens on melanocytes decreased to similar levels as in normal skin when melanocytes were in direct contact with undifferentiated, but not dif ferentiated, keratinocytes. CONCLUSIONS: Undifferentiated, but not dif ferentiated, keratinocytes control growth, morphology, and antigen exp ression of melanocytes through direct cell-cell contact. These results suggest that the phenotypic characteristics of nevus and melanoma cel ls in the dermis, i.e., proliferation and expression of tumor-associat ed antigens, may be due to their loss of contact with undifferentiatio n keratinocytes.