In Vitro Models Mimicking Immune Response in the Skin

Abstract

The skin is the first line of defense of our body, and it is composed of the epidermis and dermis with diverse immune cells. Various in vitro models have been investigated to recapitulate the immunological functions of the skin and to model inflammatory skin diseases. The simplest model is a two-dimensional (2D) co-culture system, which helps understand the direct and indirect cell-to-cell interactions between immune and structural cells; however, it has limitations when observing three-dimensional (3D) interactions or reproducing skin barriers. Conversely, 3D skin constructs can mimic the human skin characteristics in terms of epidermal and dermal structures, barrier functions, cell migration, and cell-to-cell interaction in the 3D space. Recently, as the importance of neuro-immune-cutaneous interactions in the inflammatory response is emerging, 3D skin constructs containing both immune cells and neurons are being developed. A microfluidic culture device called "skin-on-a-chip," which simulates the structures and functions of the human skin with perfusion, was also developed to mimic immune cell migration through the vascular system. This review summarizes the in vitro skin models with immune components, focusing on two highly prevalent chronic inflammatory skin diseases: atopic dermatitis and psoriasis. The development of these models will be valuable in studying the pathophysiology of skin diseases and evaluating the efficacy and toxicity of new drugs.

Keywords: Atopic dermatitis; immune system; in vitro techniques; lab-on-a-chip devices; psoriasis; skin equivalent.

Fig. 1. Overview of in vitro models for mimicking cutaneous immune responses. (A) Two-dimensional co-culture systems: skin cells, immune cells, cytokines, and small molecules can be mixed and cultured together in the same culture medium. (B) Three-dimensional skin equivalents: RHE is a model of a fully differentiated epidermis without a dermal compartment; FTSE is a bi-layered skin model (epidermis and dermis). Dermis-like structures can be made from collagen gel mixed with fibroblasts, de-epidermized dermis, or self-assembled dermal sheets. Disease-associated cytokines can be added to the culture medium, and immune cells can be added inside or underneath the ECM structures. (C) Skin-on-a-chip: a microfluidic culture device that is composed of the skin and a perfusion system. Cytokines and/or immune cells can be added to the chamber of the device to reproduce inflammatory responses. RHE, reconstructed human epidermis; FTSE, full-thickness skin equivalent; ECM, extracellular matrix.

Fig. 2. Three FTSE models depending on how the dermal part of the skin is reconstructed. (A) Collagen-based model: collagen matrix and fibroblasts are co-cultured; when a dermal matrix is formed, keratinocytes are seeded on the top. (B) Dead de-epidermized dermis model: donated human skin undergoes decellularization; on top of the decellularized dermis, keratinocytes are seeded on the top. (C) Self-assembled skin substitute model: dermal fibroblasts construct dermal sheets; keratinocytes are seeded on top of the stack of dermal sheets. FTSE, full-thickness human skin equivalents.