Coexpression of keratins 13 and 16 in human keratinocytes indicates association between hyperproliferation-associated and retinoid-induced differentiation

Abstract In human skin, epidermal differentiation occurs in two ways: normal differentiation, characterized by keratin 10 expression, and alternative differentiation. Alternative differentiation can be hyperproliferation-associated differentiation (expression of keratin 16) or the reinduction of an embryonic type of differentiation (expression of keratin 13). This embryonic type of differentiation is also seen following treatment with retinoids. In the present study, the hypothesis that hyperproliferation-associated and retinoid-induced differentiation are separate processes was investigated. Two areas of normal skin were treated for 24 h with 0.1% all-trans-retinoic acid. Subsequently, one of the areas was tape-stripped and treatment was continued for 48 h. Multiparameter flow cytometry permitted simultaneous measurement of two coexpressed differentiation markers (retinoid-induced and normal differentiation or retinoid-induced and hyperproliferation-associated differentiation) and the proliferation characteristics (cells in S/G₂M phase). Concerning normal and retinoid-induced differentiation, the all-trans-retinoic acid-induced expression of keratin 13 was only seen in tape-stripped retinoid-treated skin and exclusively together with that of keratin 10. The assessment of hyperproliferation-associated and retinoid-induced differentiation showed slight expression of keratin 13 without expression of keratin 16 in tape-stripped skin. Coexpression of keratins 16 and 13 was exclusively seen in tape-stripped retinoid-treated skin. The finding that keratin 13 expression following treatment with all-trans-retinoic acid occurred exclusively in hyperproliferative skin suggests that retinoid-induced and hyperproliferation-associated differentiation are coupled. Coexpression of keratins 13 and 16 provides direct experimental evidence for this association.