GRHL3 activates FSCN1 to relax cell-cell adhesions between migrating keratinocytes during wound reepithelialization

Abstract

The migrating keratinocyte wound front is required for skin wound closure. Despite significant advances in wound healing research, we do not fully understand the molecular mechanisms that orchestrate collective keratinocyte migration. Here, we show that, in the wound front, the epidermal transcription factor Grainyhead like-3 (GRHL3) mediates decreased expression of the adherens junction protein E-cadherin; this results in relaxed adhesions between suprabasal keratinocytes, thus promoting collective cell migration and wound closure. Wound fronts from mice lacking GRHL3 in epithelial cells ( Grhl3 -cKO) have lower expression of Fascin-1 (FSCN1), a known negative regulator of E-cadherin. Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on wounded keratinocytes shows decreased wound-induced chromatin accessibility near the Fscn1 gene in Grhl3 -cKO mice, a region enriched for GRHL3 motifs. These data reveal a wound-induced GRHL3/FSCN1/E-cadherin pathway that regulates keratinocyte-keratinocyte adhesion during wound-front migration; this pathway is activated in acute human wounds and is altered in diabetic wounds in mice, suggesting translational relevance.

E‐cadherin and aquaporin‐3 are downregulated in wound edges of human chronic wounds

“…We speculate if downregulation of tight junction proteins combined with adherens junctions at the wound edge of human chronic wounds might contribute to the pathophysiology of the chronic wounds by impairing skin repair due to decreased migratory capacity of the epidermal cells as well as reduced barrier function. However, E‐cadherin expression has been found to be almost absent in the wound front in an acute wound model using human skin xenograft (21). These observations are made in the wound front with intact epidermis, without any observations from the specific wound edge (transition from intact epidermis to loss of epidermal cells).…”

“…In vitro studies of migrating epithelial cell sheets have shown that adherens junctions are essential for cells to migrate collectively (18), and that E-cadherin is tightly regulated in collective cell migration during embryonal development, tumor metastasis, and wound healing (19,20). In an acute wound model using human xenografts, a downregulation of E-cadherin is observed in the wound front (21). AQPs are pivotal players in collective cell migration and it is thought that the facilitated water permeability aids in cell shape changes required for cell migration in restricted 3D environments (22).…”

Modulation of Piezo1 influences human skin architecture and oxytocin expression

“…The involvement of Piezo1 with components of the cytoskeleton is an area that remains to be fully explored. Damages observed after the topical application of Dooku1 on skin biopsies may be the results of the lower level of E-cadherin, weakening cell-cell adhesion and E-cadherin is implicated in wound healing modulation, as epithelial cells usually trigger their "migratory machinery" upon loss of adhesion to their neighbours [29]. Existing data describe Piezo1 as a "molecular brake" regarding wound closure, to ensure effective maintenance of epithelial integrity [30].…”

“…E‐cadherin is implicated in wound healing modulation, as epithelial cells usually trigger their “migratory machinery” upon loss of adhesion to their neighbours [29]. Existing data describe Piezo1 as a “molecular brake” regarding wound closure, to ensure effective maintenance of epithelial integrity [30].…”

Immunomodulation of wound healing leading to efferocytosis

“…102 Granulation tissue can simultaneously initiate macrophage polarization toward pro-restorative polarization, fibroblast proliferation and myofibroblast differentiation, followed by wound contraction, neointimal formation and matrix deposition. 103 Poor production of granulation tissue can lead to chronic healing or even non-healing of the wound; excessive deposition of granulation tissue, such as over-proliferation of fibroblasts and/or persistence of myofibroblasts in the granulation tissue can lead to scar formation, 104 At this point, phagocytes play a role in preventing excessive deposition of collagen fibers. It has been suggested that the "eat-me" signal CRT can promote the formation of traumatic granulation tissue.…”