Single-Cell Transcriptomics of Traced Epidermal and Hair Follicle Stem Cells Reveals Rapid Adaptations during Wound Healing

Highlights•Single-cell RNA-seq identifies distinct states of Lgr5 and Lgr6 progeny upon wounding•Wound healing activates IFE-like signature and downregulates bulge genes in Lgr5 progeny•Adaptation in Lgr5 SCs occurs within 1 day, enabling them to respond to wound signals•Lgr6 SCs are already primed to respond to wound signals in unwounded healthy skinSummaryEpithelial tissues, such as the skin, rely on cellular plasticity of stem cells (SCs) from different niches to restore tissue function after injury. How these molecularly and functionally diverse SC populations respond to injury remains elusive. Here, we genetically labeled Lgr5- or Lgr6-expressing cells from the hair follicle bulge and interfollicular epidermis (IFE), respectively, and monitored their individual transcriptional adaptations during wound healing using single-cell transcriptomics. Both Lgr5 and Lgr6 progeny rapidly induced a genetic wound signature that, for Lgr5 progeny, included the remodeling of receptors to permit interactions with the wound environment, a property that Lgr6 progeny possessed even before wounding. When contributing to re-epithelialization, Lgr5 progeny gradually replaced their bulge identity with an IFE identity, and this process started already before Lgr5 progeny left the bulge. Altogether, this study reveals how different SCs respond and adapt to a new environment, potentially explaining cellular plasticity of many epithelial tissues.Graphical abstract