HS 3D-SeboSkin Model Enables the Preclinical Exploration of Therapeutic Candidates for Hidradenitis Suppurativa/Acne Inversa

Abstract

Despite the rapid development in hidradenitis suppurativa (HS) research, the immediate introduction of potent therapeutic compounds in clinical trials and the lack of definitive outcome measures have led to the discontinuation of potential therapeutic compound studies. HS is a solely human disease, and therefore, the search for preclinical human models has been given priority. The 3D-SeboSkin model, a co-culture of human skin explants with human SZ95 sebocytes as a feeder layer, has been shown to prevent the rapid degeneration of human skin in culture and has been validated for HS preclinical studies. In this work, the HS 3D-SeboSkin model has been employed to characterize cellular and molecular effects of the EMA- and FDA-approved biologic adalimumab. Adalimumab, a tumor necrosis factor-α inhibitor, was shown to target inflammatory cells present in HS lesions, inducing a prominent anti-inflammatory response and contributing to tissue regeneration through a wound healing mechanism. Adalimumab inhibited the lesional tissue expression of TNF-α, IL-3, IL-15, and MCP-3 and downregulated the secretion of IL-1α, IL-5, RANTES, MCP-2, TNF-α, TNF-β, TGF-β, and IFN-γ. In contrast, IL-6 was stimulated. The compound failed to modify abnormal epithelial cell differentiation present in the HS lesions. Patients with Hurley stage II lesions exhibited stronger expression of autophagy proteins in perilesional than in lesional skin. Adalimumab modified the levels of the pro-apoptotic proteins LC3A, LC3B, and p62 in an individual, patient-dependent manner. Finally, adalimumab did not modify the NFκB signal proteins in SZ95 sebocytes and NHK-19 keratinocytes, used to study this specific pathway. The administration of the validated HS 3D-SeboSkin model in ex vivo studies prior to clinical trials could elucidate the individual pathogenetic targets of therapeutic candidates and, therefore, increase the success rates of clinical studies, minimizing HS drug development costs.

Preservation of epidermal melanocyte integrity in an ex vivo co‐culture skin model with sebocytes

“…Similar features, albeit to a lesser extent, were observed with co‐culture with fibroblasts. These results confirm findings of previous studies that showed preservation of skin integrity in the 3D‐SeboSkin model 20,22,23 . Interestingly, basal keratinocytes of co‐cultured skin explants proliferated and migrated to cover the exposed dermal surface in the 3D‐SeboSkin and to a lesser extent in co‐culture with fibroblasts, whereas in SFM this phenomenon was absent.…”

“…These results confirm findings of previous studies that showed preservation of skin integrity in the 3D-SeboSkin model. 20,22,23 Interestingly, basal keratinocytes of cocultured skin explants proliferated and migrated to cover the exposed dermal surface in the 3D-SeboSkin and to a lesser extent in co-culture with fibroblasts, whereas in SFM this phenomenon was absent. Furthermore, the dermis in all models showed variable degrees of features of coagulative cell death in the form of paleness, decreased vasculature and fragmentation of the collagen fibres but without inflammatory infiltrate due to absence of the blood circulation 27,28 (Figures S2 and S3).…”

“…The 3D-SeboSkin model for maintaining human skin explants ex vivo, 20,22,23 has been adapted for the assessment of epidermal melanocytes in explants from normal skin (Data S1).…”

“…20 In this model, SZ95 sebocytes are used as feeder layer for the skin explants to maintain the integrity of the epidermal keratinocytes for 6 days, thus enabling examination of several physiological and pathological conditions, such as hidradenitis suppurativa, to be examined in an ex vivo milieu. [20][21][22][23] The aim of this study was to assess the epidermal melanocytes in the 3D-SeboSkin model.…”

“…Recently, the 3D‐SeboSkin model was established to maintain human skin ex vivo and delay the rapid degenerative events that were observed during maintenance of human skin explants in culture 20 . In this model, SZ95 sebocytes are used as feeder layer for the skin explants to maintain the integrity of the epidermal keratinocytes for 6 days, thus enabling examination of several physiological and pathological conditions, such as hidradenitis suppurativa, to be examined in an ex vivo milieu 20–23 . The aim of this study was to assess the epidermal melanocytes in the 3D‐SeboSkin model.…”