Cutaneous wound reepithelialization is compromised in mice lacking functional Slug (Snai2)

Abstract

Background Keratinocytes at wound margins undergo partial epithelial to mesenchymal transition (EMT). Based on previous in vitro and ex vivo findings, Slug (Snai2), a transcriptional regulator of EMT in development, may play an important role in this process. Objectives This study was designed to validate an in vivo role for Slug in wound healing. Methods Excisional wounds in Slug null and wild type mice were examined histologically at 6, 24, 48, and 72 h after wounding; reepithelialization was measured and immunohistochemistry for keratins 8, 10, 14, and 6 and E-cadherin was performed. In 20 Slug null and 20 wild type mice exposed three times weekly to two minimal erythemal doses of UVR, the development of non-healing cutaneous ulcers was documented. Ulcers were examined histologically and by immunohistochemistry. Results The reepithelialization component of excisional wound healing was reduced 1.7-fold and expression of the Slug target genes keratin 8 and E-cadherin was increased at wound margins in Slug null compared to wild type mice. In contrast, no differences in expression of keratins 10 or 14 or in markers of proliferation K6 and Ki-67 were observed. Forty per cent of Slug null mice but no wild type mice developed non-healing cutaneous ulcers in response to chronic UVR. Keratinocytes at ulcer margins expressed high levels of keratin 8 and retained E-cadherin expression, thus resembling excisional wounds. Conclusion Slug is an important modulator of successful wound repair in adult tissue and may be critical for maintaining epidermal integrity in response to chronic injury.

Vimentin coordinates fibroblast proliferation and keratinocyte differentiation in wound healing via TGF-β–Slug signaling

“…On day 15, Slug expression returned to similar levels in WT and VIM −/− wounds ( Fig. 2E), in accordance with previously observed kinetics of transient Slug induction in several skin-injury studies (3,29). Correspondingly, the mRNA expression of EMT-dependent markers downstream of Slug, including N-cadherin (Cdh2), fibroblast-specific protein 1 (S100a4), and fibronectin (Fn1) (30), increased until day 9 and decreased by day 15 during normal WT wound closure (Fig.…”

“…Upon injury, keratinocytes at the wound edges form epithelial tongues that move and interact with the dermal cells and collagen-rich extracellular matrix (ECM) to reestablish coverage of the wound bed via a complex process termed "reepithelialization" (2,3). In addition, dermal fibroblasts activated by growth factors migrate into the site of injury, where they proliferate and lay down the ECM that facilitates cell migration and tissue reconstruction (2,3).…”

SERPINE1: A Molecular Switch in the Proliferation-Migration Dichotomy in Wound-“Activated” Keratinocytes

“…2,6,[13][14][15] PAI-1 is induced in migratory cells regardless of lineage, as well as in epithelial cells undergoing epithelial-to-mesenchymal (EMT)-like transitions upon expression of the E-cadherin transcriptional repressors Snail, Slug, or E47. 16,17 Keratinocytes and other epithelia undergo at least a partial EMT following wounding or directional migration [18][19][20] with up-regulation of uPA, the uPA cell surface receptor (uPAR), and PAI-1 at the migratory front. 6 Motile cells focalize both uPA (via interaction with uPAR) and PAI-1 (upon binding to uPA/ uPAR) to the leading edge, where they function in the interrelated events of matrix restructuring and migration.…”

Generation of cardiac progenitor cells through epicardial to mesenchymal transition

“…Increased TGF-β1 levels have been linked to kidney [14], liver [15], and lung [16] fibrosis while TGF-β mediated endothelial to mesenchymal transition (EndMT) occurs in cardiac fibrosis [17]. In skin wound healing, EGF induces SNAI2 expression and keratinocytes undergo an EMT-like process and acquire a migratory phenotype [18,19]. Under certain specific stimuli, such as hypoxia and inflammation, endothelial cells can go through EndMT and transform into mesenchymal stem celllike cells able to take part in both angiogenesis and fibrosis and, therefore, new blood vessel and scar formation, respectively [20].…”