Resistance of keratinocytes to TGFβ-mediated growth restriction and apoptosis induction accelerates re-epithelialization in skin wounds

Abstract

The pleiotropic growth factor TGFβ plays an important role in regulating responses to skin injury. TGFβ targets many different cell types and is involved in all aspects of wound healing entailing inflammation,re-epithelialization, matrix formation and remodeling. To elucidate the role of TGFβ signal transduction in keratinocytes during cutaneous wound healing, we have used transgenic mice expressing a dominant negative type II TGFβ receptor exclusively in keratinocytes. We could demonstrate that this loss of TGFβ signaling in keratinocytes led to an accelerated re-epithelialization of full thickness excisional wounds accompanied by an increased proliferation in keratinocytes at the wound edge. Furthermore, we show that impaired TGFβ signaling in keratinocytes reduces apoptosis in re-epithelialized wounds of transgenic animals. A cDNA array identified the transcription factor early growth response factor 1 (Egr1) as a target gene for TGFβ in late phases of the wound healing process. As a member of the immediate-early gene family, Egr1 is upregulated shortly after injury and induces the expression of growth factor genes. We could demonstrate that Egr1 expression is also upregulated in skin wounds which have already undergone re-epithelialization. In conclusion, we attribute the enhanced re-epithelialization in our transgenics to the resistance of keratinocytes to TGFβ-mediated growth restriction and apoptosis induction. We also propose a new role for TGFβ induced Egr1 in late phase wound repair.