Development of an immunocompetent three-dimensional (3D) skin tissue equivalent for skin fibrosis drug screening 2112

Abstract Description The skin protects the host from external insults by acting as a physical, chemical and microbiological barrier. Injury to the skin initiates a cascade of events including inflammation, proliferation, and tissue remodeling. Dysregulation of these processes can evolve into irreversible fibrotic response leading to tissue hardening. There are many etiologies of fibrotic disorders, and it is known that macrophages are pivotal in the initiation, progression, and resolution of fibrosis. The majority of the in vitro two-dimensional cultures currently used for pre-clinical drug testing lack clinical predictability because of low physiological relevance. Furthermore, skin in animals has large structural and functional differences compared to human skin. Therefore, there is a need to develop immunocompetent 3D skin tissues as a preclinical platform for skin disease modeling and drug screening. Here, we generated an immunocompetent 3D full thickness skin (FTS) tissue by introducing human macrophages into the skin construct. We showed that this macrophage-incorporated FTS responds to bacterial stimuli by producing pro- and anti-inflammatory cytokines. Furthermore, introduction of M2 macrophages into the FTS potentiates collagen deposition and myofibroblast expression upon TGFβ1 treatment, modeling a skin fibrosis phenotype. This immunocompetent 3D skin model will be a powerful platform for pre-clinical drug screening for skin fibrosis. Funding Sources Supported by NIH Intramural Research Program Topic Categories Translational and Interventional Immunology (TI)