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.

3D bioprinting of functional human skin: production and in vivo analysis

“…This model recapitulates faithfully the characteristics of the skin from which human cells were obtained (donor's skin) and overcomes the time limitations imposed by the dorsal skin full chamber used in reference [44]. Our laboratory has extensive experience, and uses it to model diverse cutaneous diseases [45] and processes [60,61]. To our knowledge, it constitutes the best system to perform long-term experiments with human skin in an in vivo scenario.…”

Development of a Bioengineered Skin-Humanized Mouse Model for Psoriasis

“…6,7,27 Regenerated normal human skin responded effectively to stimuli such as wound healing and UV-light irradiation. 28,29 We were also able to deconstruct-reconstruct several inherited skin disorders using patient derived cells. 9,10,29,30 Finally, it is also important to mention that this bioengineered skin equivalent has been widely used for permanent skin regeneration in patients suffering severe skin losses.…”

“…28,29 We were also able to deconstruct-reconstruct several inherited skin disorders using patient derived cells. 9,10,29,30 Finally, it is also important to mention that this bioengineered skin equivalent has been widely used for permanent skin regeneration in patients suffering severe skin losses. 7,31 In the present study, we move another step forward by introducing in this well-characterized skin humanized mouse model specific cytokine-producing lymphocytes to model a complex skin disease, such as psoriasis, in which the immune component plays a central role.…”

Skin Bioengineering: Preclinical and Clinical Applications

“…The genodermatoses that have been studied in this way include skin fragility diseases, such as epidermolysis bullosa, 28---30 in which blistering occurs spontaneously or following minimal trauma, and skin diseases such as xeroderma pigmentosum, in which mutations in DNA repair enzymes make the affected individuals cancer prone. 31 The model has also been used in the study of genetic diseases affecting proliferation and differentiation patterns, such as pachyonychia congenita 32 and Netherton syndrome, 33 respectively. Our team, working with several European groups, has managed to correct cells from patients with some of these conditions using various gene-therapy approaches.…”