Sphingolipid metabolism orchestrates the establishment of the adult hair follicle stem cell niche to control skin homeostasis
Bioactive sphingolipids serve as an essential building block of membranes, forming a selective barrier ensuring subcellular compartmentalization and facilitating cell type-specific intercellular communication through regulation of the plasma membrane receptor repertoire. How the 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 the skin epidermis. Deletion of CerS4 in the epidermis prevents the effective establishment of the adult hair follicle bulge stem cell (HFSCs) niche due to altered differentiation trajectories of HFSC precursors towards upper hair follicle and inner bulge fates. Mechanistically, the HFSC differentiation defects arise from a stem cell intrinsic imbalance of key ceramides and sphingolipids, and associated hyperactivity of canonical Wnt signaling. The lack of HFSCs leads to disruption of hair follicle architecture and hair follicle barrier function, ultimately triggering a Th2-dominated immune infiltration closely resembling human atopic dermatitis. This work uncovers a fundamental role for a cell state-specific sphingolipid profile in epidermal stem cell homeostasis and the role of an intact stem cell niche in maintaining an intact skin barrier. Overall design: C57BL/6N mice with floxed CerS4 alleles were generated in cooperation with Taconic Artemis (Cologne, Germany). CerS4 complete knockout mice were generated as described before (Peters et al, 2015). To achieve epidermis-specific deletion, CerS4fl/fl mice were crossed to K14-Cre mice (Hafner et al, 2004), as described before (Peters et al, 2015). Experiments were performed with CerS4fl/flK14Cre+ (termed: CerS4epi-/-) and CerS4fl/flK14Cre- (termed: ctr) male and female littermates at the indicated postnatal days (P)