1312 Nrf2 activation enhances the healing of cutaneous wounds through the activation of hair follicle stem cells

Abstract

The transcription factor Nrf2 is a key regulator of the cellular stress response through the regulation of antioxidant enzymes, cytoprotective proteins and various transporters. Strong genetic activation of Nrf2 in keratinocytes leads to a pilosebaceous phenotype, characterized by hyperplasia of the sebaceous glands and infundibula, hyperkeratosis, and seborrhea, implicating Nrf2 in several other key processes in the epidermis. Here we show that Nrf2 activation in keratinocytes promotes the proliferation and expansion of the junctional zone (JZ) and upper isthmus (UI) hair follicle stem cells, while bulge stem cells are only mildly affected. This was observed to be functionally important for wound repair, since Nrf2 activation also led to the faster closure of excisional wounds through the formation of a longer and larger wound epithelium. This however, was neither due to changes in proliferation or apoptosis of keratinocytes in the wound epithelium, nor their migration as measured in vitro. Instead, an increased number and proliferation of follicular JZ and UI stem cells were observed peripheral to the wound. An enhancement of wound healing in Nrf2 transgenic mice following tape stripping of the epidermis revealed a functional link between the Nrf2-mediated expansion of hair follicles stem cells and accelerated re-epithelialization. The effect of Nrf2 activation on JZ and UI stem cells resulted from the Nrf2-mediated up-regulation of the EGF family member Epigen and subsequent EGF receptor activation. These results suggest pharmacological Nrf2 activation as a promising approach for the enhancement of wound healing through expansion of hair follicle stem cell pools.