Loss of epidermal hypoxia-inducible factor-1α accelerates epidermal aging and affects re-epithelialization in human and mouse

In mouse and human skin, HIF-1 alpha is constitutively expressed in the epidermis, mainly in the basal layer. HIF-1 alpha has been shown to have crucial systemic functions: regulation of kidney erythropoietin production in mice with constitutive HIF-1 alpha epidermal deletion, and hypervascularity following epidermal HIF-1 alpha overexpression. However, its local role in keratinocyte physiology has not been clearly defined. To address the function of HIF-1 alpha in the epidermis, we used the mouse model of HIF-1 alpha knockout targeted to keratinocytes (K14-Cre/Hif1a(flox/flox)). These mice had a delayed skin phenotype characterized by skin atrophy and pruritic inflammation, partly mediated by basement membrane disturbances involving laminin-332 (Ln-332) and integrins. We also investigated the relevance of results of studies in mice to human skin using reconstructed epidermis and showed that HIF-1 alpha knockdown in human keratinocytes impairs the formation of a viable reconstructed epidermis. A diminution of keratinocyte growth potential, following HIF-1 alpha silencing, was associated with a decreased expression of Ln-322 and alpha 6 integrin and beta 1 integrin. Overall, these results indicate a role of HIF-1 alpha in skin homeostasis especially during epidermal aging.