Developmental transcription factor slug is required for effective re‐epithelialization by adult keratinocytes

TLDR

During cutaneous wound re‑epithelialization, keratinocytes undergo EMT‑like changes, and the transcription factor Slug, known to modulate EMT in embryos and regulate desmosome number in adult epithelium, is a key regulator. The study investigates Slug expression and function during cutaneous wound re‑epithelialization. Slug is upregulated at wound margins and promotes keratinocyte migration, spreading, and desmosome remodeling; its loss impairs re‑epithelialization while ectopic expression accelerates wound closure. © 2004 Wiley‑Liss, Inc.

Abstract

Abstract During re‐epithelialization of cutaneous wounds, keratinocytes recapitulate several aspects of the embryonic process of epithelial‐mesenchymal transition (EMT), including migratory activity and reduced intercellular adhesion. The transcription factor Slug modulates EMT in the embryo and controls desmosome number in adult epithelial cells, therefore, we investigated Slug expression and function during cutaneous wound re‐epithelialization. Slug expression was elevated in keratinocytes bordering cutaneous wounds in mice in vivo, in keratinocytes migrating from mouse skin explants ex vivo, and in human keratinocytes at wound margins in vitro. Expression of the related transcription factor Snail was not significantly modulated in keratinocytes during re‐epithelialization in vitro. Epithelial cell outgrowth from skin explants of Slug knockout mice was severely compromised, indicating a critical role for Slug in epithelial keratinocyte migration. Overexpression of Slug in cultured human keratinocytes caused increased cell spreading and desmosomal disruption, both of which were most pronounced at wound margins. Furthermore, in vitro wound healing was markedly accelerated in keratinocytes that ectopically expressed Slug. Taken together, these findings suggest that Slug plays an important role during wound re‐epithelialization in adult skin and indicate that Slug controls some aspects of epithleial cell behavior in adult tissues as well as during embryonic development. © 2004 Wiley‐Liss, Inc.