Abstract
Sphingolipids serve as building blocks of membranes to ensure subcellular compartmentalization and facilitate intercellular communication. How cell type-specific lipid compositions are achieved and what is their functional significance in tissue morphogenesis and maintenance has remained unclear. Here, we identify a stem cell-specific role for ceramide synthase 4 (CerS4) in orchestrating fate decisions in skin epidermis. Deletion of CerS4 prevents the proper development of the adult hair follicle bulge stem cell (HFSC) compartment due to altered differentiation trajectories. Mechanistically, HFSC differentiation defects arise from an imbalance of key ceramides and their derivate sphingolipids, resulting in hyperactivation of noncanonical Wnt signaling. This impaired HFSC compartment establishment leads to disruption of hair follicle architecture and skin barrier function, ultimately triggering a T helper cell 2-dominated immune infiltration resembling human atopic dermatitis. This work uncovers a fundamental role for a cell state-specific sphingolipid profile in stem cell homeostasis and in maintaining an intact skin barrier.