Abstract
In the wound healing process, the morphology of keratinocytes at the wound edge temporarily changes to a spindle morphology, which is thought to occur due to an epithelial–mesenchymal transition (EMT). Fibroblast growth factor (FGF) 2, also called basic FGF, has the potential to accelerate wound closure by activating vascular endothelial cells and fibroblasts. We examined the effects of FGF2 on keratinocyte morphology and EMT in wounded skin. Histological examination of murine wounds treated with FGF2 revealed that wound edge keratinocytes formed thickened and multilayered epithelia. In addition, we detected wound edge keratinocytes migrating individually toward the wound center. These migrating keratinocytes exhibited not only spindle morphology but also down-regulated E-cadherin and up-regulated vimentin expression, which is characteristic of EMT. In FGF2-treated wounds, a PCR array revealed the upregulation of genes related to EMT, including transforming growth factor (TGF) signaling. Further, FGF2-treated wound edge keratinocytes expressed EMT-associated transcription factors, including Snai2, and showed translocation of β-catenin from the cell membrane to the cytoplasm/nucleus. However, in vitro examination of keratinocytes revealed that FGF2 alone did not activate EMT in keratinocytes, but that FGF2 might promote EMT in combination with TGFβ1. These findings suggest that FGF2 treatment of wounds could promote keratinocyte EMT, accelerating wound closure.
Highlights
In the wound healing process, the morphology of keratinocytes at the wound edge temporarily changes to a spindle morphology, which is thought to occur due to an epithelial–mesenchymal transition (EMT)
The numbers of keratinocytes layer of wound edge were increased in FGF2-treated wounds, with an average of 12.5 ± 2.5 keratinocytes in the FGF2-treated group and 7.0 ± 1.5 keratinocytes in the control group (p < 0.01; Fig. 1d)
At day 4 after induction of skin wounds, histological examination revealed that keratinocytes in FGF2-treated wounds protruded from the surface, and that spindle-shaped keratinocytes migrated from the wound edge into fibrin clots or granulation tissue (Fig. 1e)
Summary
In the wound healing process, the morphology of keratinocytes at the wound edge temporarily changes to a spindle morphology, which is thought to occur due to an epithelial–mesenchymal transition (EMT). Reepithelization is a phenomenon in the new tissue formation process in which keratinocytes migrate from the wound edge to the wound center on regenerated granulation tissue, driven by growth factors and cytokines released from sites of injury. In both in vitro and in vivo models, wound edge keratinocytes prepare for migration to the wound center through molecular, morphological, cytoskeletal and adhesive changes[4,5,6]. Most in vitro studies have reported that FGF2 is less active in keratinocytes that are derived from primitive ectoderm, relative to mesoderm-derived c ells[28]
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