Identification of superoxide dismutase 3 as a critical factor for dermal stem cell maintenance

Background: Dermal stem cells (DSCs) act as fibroblast progenitors essential for maintaining skin structure and wound healing. However, the molecular mechanisms governing DSC maintenance remain unclear. Objective: This study aimed to elucidate the factors involved in DSC maintenance. Methods: Age-related changes in CD271-positive DSC count were determined by immunohistochemical staining. Primary dermal cells derived from participants categorized as either DSC-rich or DSC-poor underwent proteomic analysis. The expression of superoxide dismutase 3 (SOD3) in the dermis and DSCs was evaluated using immunostaining and quantitative RT-PCR (qRT-PCR). Additionally, a knockdown experiment was conducted to clarify SOD3 involvement in DSC maintenance. Results: DSC count decreased with age. In proteomic analysis, DSC-rich dermal cells displayed high SOD3 expression. Furthermore, DSCs had significantly higher SOD3 expression than nonstem cells, contributing to higher SOD3 levels in DSC-rich dermis. Inducing the differentiation of DSCs into fibroblasts decreased SOD3 gene expression. SOD3 knockdown in DSCs increased reactive oxygen species (ROS) levels and DNA damage, causing downregulation of DNA repair genes and stem cell marker genes and upregulation of fibroblast marker genes. However, treatment with recombinant SOD3 protein or ascorbic acid resolved these phenotypes. Conclusion: SOD3 is a protein essential for maintaining DSCs. The findings of this study offer a new perspective on the molecular mechanisms underlying skin aging and suggest SOD3 as a potential therapeutic target.