Dysregulation of Cell Adhesion in Epidermal Stem Cells of Prurigo Nodularis Reduces Their Proliferative Capacity

ABSTRACT The development of biomaterials provides a promising avenue for uncovering pathogenic mechanisms and exploring novel therapeutic strategies, particularly for refractory dermatoses, such as prurigo nodularis (PN), a chronic pruritic dermatosis of unknown etiopathogenesis. Although immune cells play important roles in skin inflammation, few studies have investigated the pathogenesis of PN from the perspective of the interaction between basal layer epidermal stem cells (EpSCs) and the basement membrane (BM) extracellular matrix (ECM). In this study, we used quantitative proteomic techniques to construct protein expression profiles of EpSCs and their extracellular vesicles from patients with PN. By combining protein‒protein interaction networks and pathological analyses, we investigated the relationships among EpSCs, EpSC‐derived exosomes, and the immune microenvironment of PN. EpSCs exhibited abnormal morphology in patients with PN, with EpSC dysfunction mediated by the activation of inflammasome pathways. To further analyze these mechanisms, we employed biomaterial‐based models, including multiple models of tissue‐engineered skin and 3D epidermal organoids. These results revealed that regulating cell‒matrix adhesion between basal layer EpSCs and the BM ECM promoted the function of EpSCs, making this regulation a potential target for the treatment of PN EpSC dysfunction.