The role of Wisp1 in epithelial dysfunction in chronic rhinosinusitis
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Chronic rhinosinusitis (CRS) is a chronic inflammatory disease that can be subdivided into chronic rhinosinusitis sans nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD). Nasal polyps are a hallmark feature of CRSwNP and AERD. Although, the pathophysiology of polypogenesis is thought to be multifactorial, type 2 (allergic-type) immune responses and epithelial remodeling are considered to be central features. In polyp disease, epithelial remodeling and dysfunction leads to decreased epithelial diversity, with increased basal cells and decreased goblet and ciliated cells. A role for Wnt signaling is well established in cancer and fibrotic diseases, and recent studies have indicated that Wnt signaling is also upregulated in sinonasal polyposis, a non-cancerous disease. Wisp1, a downstream mediator of the Wnt pathway, is significantly increased in polyp disease compared to non-polyp disease. Wnt pathway ligands have been reported to induce the proliferation and impair differentiation of airway basal cells, but the direct effect of the downstream Wnt pathway gene, Wisp1, on respiratory basal epithelial cells is unknown. This study aims to investigate the role of Wisp1 on the proliferation, cell migration, and differentiation of human respiratory epithelial cells. In the current study, we found increased expression of WISP1 in nasal polyps examined directly ex vivo. Histological analysis of nasal polyps and WISP1 expression in primary basal epithelial cell cultures suggested epithelial production of Wisp1 as a feature of nasal polyposis. Using submerged and air-liquid interface (ALI) cell cultures, the effect of Wisp1 on proliferation, cell migration and differentiation was investigated. Increased basal cell accumulation and loss of differentiation are hallmarks of sinonasal polyposis. The chronic inflammatory environment present in polyp disease includes chronic increased WISP1 expression, which endorses a role for this protein in disease. The results of this study suggest that prolonged exposure to Wisp1 may lead to an increase in the cellular mass of respiratory basal epithelial cells, while limiting their ability to differentiate, thus allowing for unchecked accumulation. Taken together, our results suggest that Wisp1 may contribute to central features of nasal polyposis, thus identifying this protein as a potential target for future therapeutic intervention.