Lineage and renewal dynamics of sebaceous glands govern skin barrier integrity in mice.

Sebaceous glands (SGs) are essential for maintaining skin homeostasis and barrier function. However, the cell biology and lineage of SGs remain poorly understood in vivo. Here we performed bulk isolation of murine SGs, uncovered their molecular features, and generated SG-specific tool mouse models. Tracing with SG-Chaser mice revealed SG heterogeneity and their dynamic and distinct responses to common external stimuli. Specifically, some SG stem cell (SGSC) descendants homed back to the bulge and underwent redifferentiation, the toggling of which is critical for preserving stem cell pool and maintaining SG homeostasis. Combining single-cell RNA sequencing with lineage tracing, we identified the origin of murine SGs and found that Krt15+ cells gave rise to both typical and atypical SGs via divergent differentiation trajectories. As lipid-rich cells, murine sebocytes exhibit a differentiation program closely resembling that of adipocytes and highly reliant on Pparγ. Topical pharmacological regulation of Pparγ can effectively modulate sebocytes homeostasis in both mice and humans. Together, these results unveil the multilayered dynamics of murine SGs and suggest viable approaches to modulate SG homeostasis and maintain barrier integrity.