Sphingolipid Metabolism Orchestrates the Establishment of the Adult Hair Follicle Stem Cell Niche to Control Skin Homeostasis

This study identifies a crucial role for ceramide synthase 4 (CerS4) in the development of the adult hair follicle stem cell (HFSC) niche, which is essential for skin homeostasis. The deletion of CerS4 in the epidermis leads to improper development of the HFSC niche, as HFSC precursors are misdirected towards different cell fates, which is attributed to an imbalance of ceramides and sphingolipids. This imbalance results in hyperactive Wnt signaling, causing defects in HFSC differentiation. Consequently, the architecture and barrier function of hair follicles are compromised, leading to a T helper cell 2-dominated immune response that resembles human atopic dermatitis. The findings highlight the importance of specific sphingolipid profiles in epidermal stem cell maintenance and the necessity of a functional stem cell niche for a healthy skin barrier.