Gate keeping the sebaceous gland

Sebaceous gland (SG) secretions are pivotal to skin and eye health. At the SG-epidermis confluence is an overlooked epidermal collar we named the follicular epidermis (FE). Here, we show that the FE is similar among different SG types and contains unique Axin2+ stem cells in a niche at its basal FE-perpendicular flexure (FE-PF). Lineage tracing and ablation assays demonstrate Axin2+ cells as integral for FE homeostasis. Wnt-secretion arrest experiments resulted in FE-obstruction via hyperproliferation and inhibited differentiation inferring FE-PF Axin2+ cells are Wnt-producers maintaining FE-patency. Upon constitutive Axin2+ cell Wnt signalling, FE-PF-specific cell proliferation with early-stage signs of malignancy formed alongside a keratin-plugging FE-obstruction type. While keratin-based obstructions are recognized, inhibited differentiation obstructions are not, which suggests a one-size-fits-all therapeutic approach is not optimal. We offer a molecular identification toolkit to aid anti-obstruction advances in dermatology/ophthalmology and highlight the FE-PF as a skin tumorigenic site. Summary This work characterises a novel site in the skin, it’s stem cells and niche, a site prone to cancer. Obstructions can occur at this site by two mechanisms, one of which is novel, bringing into question current therapy and prompting a rethink of disease in dermatology and ophthalmology to account for this novel site. Graphical Abstract