title: In vivo assessment of acute UVB responses in normal and Xeroderma Pigmentosum (XP-C) skin-humanized mouse models.
abstract: In vivo studies of UVB effects on human skin are precluded by ethical and technical arguments on volunteers and inconceivable in cancer-prone patients such as those affected with Xeroderma Pigmentosum (XP). Establishing reliable models to address mechanistic and therapeutic matters thus remains a challenge. Here we have used the skin-humanized mouse system that circumvents most current model constraints. We assessed the UVB radiation effects including the sequential changes after acute exposure with respect to timing, dosage, and the relationship between dose and degree-sort of epidermal alteration. On Caucasian-derived regenerated skins, UVB irradiation (800 J/m(2)) induced DNA damage (cyclobutane pyrimidine dimers) and p53 expression in exposed keratinocytes. Epidermal disorganization was observed at higher doses. In contrast, in African descent-derived regenerated skins, physiological hyperpigmentation prevented tissue alterations and DNA photolesions. The acute UVB effects seen in Caucasian-derived engrafted skins were also blocked by a physical sunscreen, demonstrating the suitability of the system for photoprotection studies. We also report the establishment of a photosensitive model through the transplantation of XP-C patient cells as part of a bioengineered skin. The inability of XP-C engrafted skin to remove DNA damaged cells was confirmed in vivo. Both the normal and XP-C versions of the skin-humanized mice proved proficient models to assess UVB-mediated DNA repair responses and provide a strong platform to test novel therapeutic strategies.
authors.affiliation: Cutaneous Regenerative Medicine Unit, Epithelial Biomedicine Division, CIEMAT, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: García
authors.forename: Sara
authors.initials: S
authors.lastname: Llames
authors.forename: Eva
authors.initials: E
authors.lastname: García
authors.forename: Alvaro
authors.initials: A
authors.lastname: Meana
authors.forename: Natividad
authors.initials: N
authors.lastname: Cuadrado
authors.forename: Mar
authors.initials: M
authors.lastname: Recasens
authors.forename: Susana
authors.initials: S
authors.lastname: Puig
authors.forename: Eduardo
authors.initials: E
authors.lastname: Nagore
authors.forename: Nuria
authors.initials: N
authors.lastname: Illera
authors.forename: José Luis
authors.initials: JL
authors.lastname: Jorcano
authors.forename: Marcela
authors.initials: M
authors.lastname: Del Rio
authors.forename: Fernando
authors.initials: F
authors.lastname: Larcher
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D006801:Humans; D015603:Keratinocytes / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D011740:Pyrimidine Dimers / Q000235:genetics; D012867:Skin / Q000166:cytology / Q000473:pathology / Q000528:radiation effects*; D012880:Skin Pigmentation; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014983:Xeroderma Pigmentosum / Q000473:pathology*
chemical_list: D011740:Pyrimidine Dimers