Stimulation of human epidermal differentiation by Delta-Notch signalling at the boundaries of stem-cell clusters

Background: Human epidermis is renewed throughout life from stem cells in t he basal layer of the epidermis, Signals from the surrounding keratinocytes influence the differentiation of the stem cells, but the nature of the sig nals is unknown. In many developing tissues, signalling mediated by the tra nsmembrane protein Delta1 and its receptor Notch1 inhibits differentiation. Here, we investigated the role of Delta-Notch signalling in postnatal huma n epidermis. Results: Notch1 expression was found in all living epidermal layers, but De lta1 expression was confined to the basal layer of the epidermis, with high est expression in those regions where stem cells reside. By overexpressing Delta1 or Delta(T), a truncated form of Delta1, in primary human keratinocy tes and reconstituting epidermal sheets containing mixtures of Delta-overex pressing cells and wild-type cells, we found that cells expressing high lev els of Delta1 or Delta(T) failed to respond to Delta signals from their nei ghbours. In contrast, wild-type keratinocytes that were in contact with nei ghbouring cells expressing Delta1 were stimulated to leave the stem-cell co mpartment and initiate terminal differentiation after a few rounds of divis ion. Delta1 promoted keratinocyte cohesiveness, whereas Delta(T) did not. Conclusions: We propose that high Delta1 expression by epidermal stem cells has three effects: a protective effect on stem cells by blocking Notch sig nalling; enhanced cohesiveness of stem-cell clusters, which may discourage intermingling with neighbouring cells; and signalling tp cells at the edges of the clusters to differentiate. Notch signalling in epidermal stem cells thus differs from other progenitor cell populations in promoting, rather t han suppressing, differentiation.