In vitro psoriasis models with focus on reconstructed skin models as promising tools in psoriasis research

Abstract

Psoriasis is a complex chronic immune-mediated inflammatory cutaneous disease associated with the development of inflammatory plaques on the skin. Studies proved that the disease results from a deregulated interplay between skin keratinocytes, immune cells and the environment leading to a persisting inflammatory process modulated by pro-inflammatory cytokines and activation of T cells. However, a major hindrance to study the pathogenesis of psoriasis more in depth and subsequent development of novel therapies is the lack of suitable pre-clinical models mimicking the complex phenotype of this skin disorder. Recent advances in and optimization of three-dimensional skin equivalent models have made them attractive and promising alternatives to the simplistic monolayer cultures, immunological different in vivo models and scarce ex vivo skin explants. Moreover, human skin equivalents are increasing in complexity level to match human biology as closely as possible. Here, we critically review the different types of three-dimensional skin models of psoriasis with relevance to their application potential and advantages over other models. This will guide researchers in choosing the most suitable psoriasis skin model for therapeutic drug testing (including gene therapy via siRNA molecules), or to examine biological features contributing to the pathology of psoriasis. However, the addition of T cells (as recently applied to a de-epidermized dermis-based psoriatic skin model) or other immune cells would make them even more attractive models and broaden their application potential. Eventually, the ultimate goal would be to substitute animal models by three-dimensional psoriatic skin models in the pre-clinical phases of anti-psoriasis candidate drugs. Impact statement The continuous development of novel in vitro models mimicking the psoriasis phenotype is important in the field of psoriasis research, as currently no model exists that completely matches the in vivo psoriasis skin or the disease pathology. This work provides a complete overview of the different available in vitro psoriasis models and suggests improvements for future models. Moreover, a focus was given to psoriatic skin equivalent models, as they offer several advantages over the other models, including commercial availability and validity. The potential and reported applicability of these models in psoriasis pre-clinical research is extensively discussed. As such, this work offers a guide to researchers in their choice of pre-clinical psoriasis model depending on their type of research question.

Towards the development of a RNAi‐based topical treatment for psoriasis: Proof‐of‐concept in a 3D psoriasis skin model

“…Using this reconstructed skin model as disease model for psoriasis, we were limited in the assessment of a therapeutic effect on the skin morphology as the model does not represent all histological features typical to psoriasis. [31,46] Therapeutic efficacy of the combination therapy was nevertheless apparent since reduced expression of the differentiation marker involucrin and keratinization marker elafin was shown. Surprisingly, no enhanced therapeutic effect was established when using the siRNA mix as compared to the single siRNAs.…”

3D organ models—Revolution in pharmacological research?

“…Notably, although epithelial models of the skin or the upper airways belong to the most advanced organ models, publications describing their use for drug testing are scarce. Most studies reporting novel epithelial models conclude that these are promising tools for preclinical testing in vitro [51][52][53] without presenting any data to support this. More studies still have been published with regard to drug delivery approaches [54,55], but without including clear pharmacological readouts.…”

Translational drug discovery and development with the use of tissue‐relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy

“…Target identification and validation remain a pressing challenge in the pharmaceutical industry [79] even for psoriasis. In that context, the use of either non-diseased [85] or diseased [86] human skin appears preferable for drug testing as almost all available full-thickness skin equivalents, despite the addition of immune cells, remain at risk of being artificial, [87] since the available models may not express the genes characteristic for human psoriatic skin. Healthy human skin, lesional and uninvolved skin samples have been characterized.…”

“…[87] Compounds are tested with high-throughput screening by using cells expressing the target to obtain data about target affinity, selectivity and cytotoxity. [87] Compounds are tested with high-throughput screening by using cells expressing the target to obtain data about target affinity, selectivity and cytotoxity.…”