Overexpression of mIGF-1 in keratinocytes improves wound healing and accelerates hair follicle formation and cycling in mice

Insulin-like growth factor 1 (IGF-1) is an important regulator of growth, survival, and differentiation in many tissues. It is produced in several isoforms that differ in their N-terminal signal peptide and C-terminal extension peptide. The locally acting isoform of IGF-1 (mIGF-1) was previously shown to enhance the regeneration of both muscle and heart. In this study, we tested the therapeutic potential of mIGF-1 in the skin by generating a transgenic mouse model in which mIGF-1 expression is driven by the keratin 14 promoter. IGF-1 levels were unchanged in the sera of hemizygous K14/mIGF-1 transgenic animals whose growth was unaffected. A skin analysis of young animals revealed normal architecture and thickness as well as proper expression of differentiation and proliferation markers. No malignant tumors were formed. Normal homeostasis of the putative stem cell compartment was also maintained. Healing of full-thickness excisional wounds was accelerated because of increased proliferation and migration of keratinocytes, whereas inflammation, granulation tissue formation, and scarring were not obviously affected. In addition, mIGF-1 promoted late hair follicle morphogenesis and cycling. To our knowledge, this is the first work to characterize the simultaneous, stimulatory effect of IGF-1 delivery to keratinocytes on two types of regeneration processes within a single mouse model. Our analysis supports the use of mIGF-1 for skin and hair regeneration and describes a potential cell type-restricted action

Keratinocyte-derived follistatin regulates epidermal homeostasis and wound repair

Activin is a growth and differentiation factor that controls development and repair of several tissues and organs. Transgenic mice overexpressing activin in the skin were characterized by strongly enhanced wound healing, but also by excessive scarring. In this study, we explored the consequences of targeted activation of activin in the epidermis and hair follicles by generation of mice lacking the activin antagonist follistatin in keratinocytes. We observed enhanced keratinocyte proliferation in the tail epidermis of these animals. After skin injury, an earlier onset of keratinocyte hyperproliferation at the wound edge was observed in the mutant mice, resulting in an enlarged hyperproliferative epithelium. However, granulation tissue formation and scarring were not affected. These results demonstrate that selective activation of activin in the epidermis enhances reepithelialization without affecting the quality of the healed wound

Systemic decreases in cutaneous innervation after burn injury

A letter to the Editor of the Journal of Investigative Dermatology Innervation of the skin is important in order to maintain functional sensation and enable appropriate response to environmental stimuli. Injury to the skin may involve peripheral nerve damage. Previous studies have shown an initial loss of nerve fibers followed by an increase above normal fiber density, which is followed by apoptosis and ultimately reduced innervation and sensory function in scar tissue (Hermanson et al., 1987; Stella et al., Supp.(767) 1994; Altun et al., 2001; Ward et al., 2004; Nedelec et al., 2005). Although some studies have found an association between reduced nerve density and sensation (Stella et al., 1994; Ward et al., 2004), other studies have not (Griffin et al., 2001; Nedelec et al., 2005). The contradictory nature of these findings is at least in part due to small sample numbers, incomplete functional and anatomical assessment, and the variable timeframes between injury and analysis. Herein, to better understand the changes in cutaneous innervation and sensory function, we have analyzed neuroanatomy in a rat model of burn injury, and assessed neuroanatomy in patients with unilateral burn injuries at least 18 months post-injury, which is commonly defined as the end point for scar maturity (Nedelec et al., 2005). All animal experiments were approved by the institutional animal ethics committee and were performed in accordance with the NHMRC Australian code of practice for the care and use of animals for scientific purposes. The human study was carried out in accordance with the regulations outlined in the national statement on ethical conduct in research involving humans issued by the NHMRC and was approved by the Royal Perth Hospital ethics committee