Lgr6 marks epidermal stem cells with a nerve-dependent role in wound re-epithelialization

•Lgr6 stem cells in the skin epidermis show distinct response to injury •Ablation of Lgr6 stem cells impairs wound healing •Skin denervation alters the contribution of stem cells during wound healing •Loss of sensory nerves changes the fate of Lgr6 stem cells Stem cells support lifelong maintenance of adult organs, but their specific roles during injury are poorly understood. Here we demonstrate that Lgr6 marks a regionally restricted population of epidermal stem cells that interact with nerves and specialize in wound re-epithelialization. Diphtheria toxin-mediated ablation of Lgr6 stem cells delays wound healing, and skin denervation phenocopies this effect. Using intravital imaging to capture stem cell dynamics after injury, we show that wound re-epithelialization by Lgr6 stem cells is diminished following loss of nerves. This induces recruitment of other stem cell populations, including hair follicle stem cells, which partially compensate to mediate wound closure. Single-cell lineage tracing and gene expression analysis reveal that the fate of Lgr6 stem cells is shifted toward differentiation following loss of their niche. We conclude that Lgr6 epidermal stem cells are primed for injury response and interact with nerves to regulate their fate. Stem cells support lifelong maintenance of adult organs, but their specific roles during injury are poorly understood. Here we demonstrate that Lgr6 marks a regionally restricted population of epidermal stem cells that interact with nerves and specialize in wound re-epithelialization. Diphtheria toxin-mediated ablation of Lgr6 stem cells delays wound healing, and skin denervation phenocopies this effect. Using intravital imaging to capture stem cell dynamics after injury, we show that wound re-epithelialization by Lgr6 stem cells is diminished following loss of nerves. This induces recruitment of other stem cell populations, including hair follicle stem cells, which partially compensate to mediate wound closure. Single-cell lineage tracing and gene expression analysis reveal that the fate of Lgr6 stem cells is shifted toward differentiation following loss of their niche. We conclude that Lgr6 epidermal stem cells are primed for injury response and interact with nerves to regulate their fate.