Development of a Bioengineered Skin-Humanized Mouse Model for Psoriasis

Abstract

Over the past few years, whole skin xenotransplantation models that mimic different aspects of psoriasis have become available. However, these models are strongly constrained by the lack of skin donor availability and homogeneity. We present in this study a bioengineering-based skin-humanized mouse model for psoriasis, either in an autologous version using samples derived from psoriatic patients or, more importantly, in an allogeneic context, starting from skin biopsies and blood samples from unrelated healthy donors. After engraftment, the regenerated human skin presents the typical architecture of normal human skin but, in both cases, immunological reconstitution through intradermal injection in the regenerated skin using in vitro-differentiated T1 subpopulations as well as recombinant IL-17 and IL-22 Th17 cytokines, together with removal of the stratum corneum barrier by a mild abrasive treatment, leads to the rapid conversion of the skin into a bona fide psoriatic phenotype. Major hallmarks of psoriasis were confirmed by the evaluation of specific epidermal differentiation and proliferation markers as well as the mesenchymal milieu, including angiogenesis and infiltrate. Our bioengineered skin-based system represents a robust platform to reliably assess the molecular and cellular mechanisms underlying the complex interdependence between epidermal cells and the immune system. The system may also prove suitable to assess preclinical studies that test the efficacy of novel therapeutic treatments and to predict individual patient response to therapy. Psoriasis is a T cell-mediated inflammatory skin disorder, multifactorial in its etiology. It affects about 2% of the worldwide population. There is a wide range of clinical presentations of the disease, but the most common variety is the chronic plaque psoriasis. In many cases the severity of the outcome may have serious (disabling) physical as well as psychological consequences.1 Several transgenic and knockout mouse models of the disease have been developed to date, and they have been proved to be valuable tools to establish the contribution of specific molecules to the pathogenesis of the disease.2,3 However, none of them fully recapitulates the complex pathophysiology of human psoriasis. Moreover, human skin presents major differences with mouse skin, making it more difficult to mimic the human condition.

Targeted silencing of DEFB4 in a bioengineered skin‐humanized mouse model for psoriasis: development of siRNA SECosome‐based novel therapies

“…We have also demonstrated a strong up-regulation of this antimicrobial peptide (AMP) in the skin-humanized mouse model for psoriasis (8) as compared to the expression in control animals harbouring regenerated normal human skin (Fig. 1a).…”

“…In the dermis of the PS + DEFB4 SEC group of animals, only a few CD31/ICAM-1+ blood vessels are found. previously demonstrated to be modulated in this animal model (8) and that have been defined as biomarkers of disease activity (16). Similar staining patterns were observed in both PS and PS + DEFB4 SEC experimental groups for some differentiation (involucrin and keratin 1 expression) (Fig.…”

“…We have previously demonstrated the effectiveness of SECosomes in delivering siRNA to the viable epidermis of ex vivo human skin (11). To evaluate the therapeutic effect of silencing DEFB4 using SECosomes complexed with siRNA (SECoplexes), we used the skin-humanized mouse model for psoriasis (8) that was previously characterized in our laboratory as a valuable tool for preclinical drug discovery as well as for increasing knowledge of the basic mechanisms underlying the pathogenesis of this complex disease.…”

“…The hBD-2 antimicrobial peptide (encoded by the DEFB4 gene) has been proven to be the strongest and most psoriasis-specific protein, thus being a promising target for therapeutic purposes (6,7). Herein, we used siRNA complexed to ultraflexible nanosomes (SECosomes) to explore the effect of inhibiting hBD-2 expression on a bioengineered skin-humanized mouse model for psoriasis (8). The use of both technologies may provide a valuable preclinical tool to assess the effect of targeting key molecules in the pathogenesis of psoriasis.…”

Immunological Considerations for Inducing Skin Graft Tolerance

“…Other aspects involving the use of these animal models to study diabetes have been reviewed (King et al, 2008. Humanized mouse models of psoriasis have been developed that use bioengineered skin derived from biopsies and from patients with psoriasis (Guerrero-Aspizua et al, 2010). A psoriasis pathology was duplicated by injecting cultivated T cell populations along with IL17and IL-22, and depriving the skin of its stratum corneum.…”