Stem cell systems underlie homeostatic tissue maintenance, yet the involvement of cell competition in organ maintenance and aging are largely unknown. Here we report that the expression of Collagen XVII (COL17A1), a hemidesmosome component, by epidermal stem cells fluctuates physiologically through genomic/oxidative stress-induced proteolysis and the resulting differential expression of COL17A1 in individual stem cells promotes cell-cell competition. In vivo clonal analysis in mice and in vitro 3D modeling revealed that COL17A1+ clones, which divide symmetrically, outcompete adjacent COL17A1llow/- stressed clones, which divide asymmetrically to select stem cells with higher potential and quality for youthfulness. Yet, eventual loss of COL17A1 limits their competition, causing aging. The resultant hemidesmosome fragility in those cells depletes adjacent epidermal melanocytes/melanoblasts and dermal fibroblasts to cause whole skin organ aging phenotypes such as skin atrophy, dys-pigmentation and defective wound healing. Conversely, the forced maintenance of COL17A1 in the murine epidermis rescues skin organ aging thereby opening a new venue for therapeutic intervention.

Epidermal stem cell competition orchestrates skin organ homeostasis and aging