title: Loss of epidermal hypoxia-inducible factor-1α accelerates epidermal aging and affects re-epithelialization in human and mouse.
abstract: In mouse and human skin, HIF-1α is constitutively expressed in the epidermis, mainly in the basal layer. HIF-1α has been shown to have crucial systemic functions: regulation of kidney erythropoietin production in mice with constitutive HIF-1α epidermal deletion, and hypervascularity following epidermal HIF-1α overexpression. However, its local role in keratinocyte physiology has not been clearly defined. To address the function of HIF-1α in the epidermis, we used the mouse model of HIF-1α 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-1α knockdown in human keratinocytes impairs the formation of a viable reconstructed epidermis. A diminution of keratinocyte growth potential, following HIF-1α silencing, was associated with a decreased expression of Ln-322 and α6 integrin and β1 integrin. Overall, these results indicate a role of HIF-1α in skin homeostasis especially during epidermal aging.
authors.affiliation: INSERM, Biothérapies des maladies génétiques et cancers, U1035, 146 rue Léo Saignat, Bordeaux,  F-33000 France.
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Rezvani
authors.forename: Nsrein
authors.initials: N
authors.lastname: Ali
authors.forename: Martin
authors.initials: M
authors.lastname: Serrano-Sanchez
authors.forename: Pierre
authors.initials: P
authors.lastname: Dubus
authors.forename: Christine
authors.initials: C
authors.lastname: Varon
authors.forename: Cécile
authors.initials: C
authors.lastname: Ged
authors.forename: Catherine
authors.initials: C
authors.lastname: Pain
authors.forename: Muriel
authors.initials: M
authors.lastname: Cario-André
authors.forename: Julien
authors.initials: J
authors.lastname: Seneschal
authors.forename: Alain
authors.initials: A
authors.lastname: Taïeb
authors.forename: Hubert
authors.initials: H
authors.lastname: de Verneuil
authors.forename: Frédéric
authors.initials: F
authors.lastname: Mazurier
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D015536:Down-Regulation; D004817:Epidermis / Q000502:physiology*; D055786:Gene Knockout Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D016023:Integrins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D012867:Skin / Q000033:anatomy & histology; D014945:Wound Healing; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016023:Integrins; D000097794:Kalinin; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse