Disorganization of basement membrane zone architecture for impaired melanocyte inhabitation in vitiligo

Vitiligo is an acquired hypomelanotic disorder characterized by the absence of melanocytes. The mechanism of melanocyte loss remains unclear. In this study, we aimed to explore the underlying mechanism. By electron microscopy and immunohistochemistry, branching and fragmented basement membranes (BM) were identified in vitiligo skin. To determine why BM was altered in vitiligo, the expression of matrix metalloproteinase 2 (MMP2) and MMP9 in vitiligo skin sections were analyzed. The upper dermis fibroblasts secreted MMP2 was dramatically increased. After transplanting fibroblasts that overexpress MMP2, BM disruption and melanocyte disappearance were observed in 3D skin equivalents and cultured ex vivo skin explants. By in situ proximity ligation assay, a dramatic decrease in integrin-laminin binding were observed, albeit no change in individual expression levels. Furthermore, immunoelectron microscopy revealed the aberrant distribution of laminin decreases integrin-laminin binding. Finally, in Krt14-Kitl mice, depigmentation patches were observed on mice’s backs by transplanting MMP2-overexpressing fibroblasts, and MMP2 inhibition reversed this depigmentation. These findings imply that elevated MMP2 production by dermal fibroblasts may play a crucial role in the loss of melanocytes in vitiligo through disruption of the melanocyte-BM junction and that MMP2 inhibitors may be an effective treatment.