LB966 Transcriptional regulation of migrating-keratinocyte adhesion during cutaneous wound healing

Abstract

The migration of wound-edge keratinocytes is part of the wound response, crucial for complete wound closure. Despite significant advances, the molecular mechanisms that orchestrate cell-cell adhesion between migrating keratinocytes are not fully characterized. During wound re-epithelization, keratinocytes at the wound edge undergo series of cellular modifications. These cellular modifications require a loosening of cell-cell adhesion for effective migration. Mice lacking the epidermal transcription factor Grainyhead Like-3 (GRHL3) exhibit impaired wound healing and an increased adhesion between keratinocytes at the wound edge. The increased cell-cell adhesion in Krt14-Cre Grhl3fl/fl wounds coincides with high expression of the adherens junction protein E-Cadherin and downregulation of the newly identified wound-response gene Fascin (FSCN1). Gene expression analysis of isolated woundedge keratinocytes shows significant downregulation of Fscn1 mRNA expression in Krt14-Cre Grhl3fl/fl wounds. In addition, ATAC-seq on Krt14-Cre Grhl3fl/fl wound-edge keratinocytes shows loss of wound-specific peaks near Fscn1 gene, in a region that is highly enriched for GRHL3 motifs. Together, these data elucidate a novel wound-specific FSCN1-E-cadherin pathway controlled by GRHL3 that is required for cell-cell loosening between migrating keratinocytes during wound re-epithelization. This pathway is altered in chronic diabetic wounds in mice.