title: Ceramide synthase 4 regulates stem cell homeostasis and hair follicle cycling.
abstract: Ceramides are crucial for skin barrier function, but little is known about the regulation of epidermal appendages and whether stem cell populations that control their regeneration depend on specific ceramide species. Here we demonstrate that ceramide synthase 4 (CerS4) is highly expressed in the epidermis of adult mice where it is localized in the interfollicular epidermis and defined populations within the pilosebaceous unit. Inactivation of CerS4 in mice resulted in precocious activation of hair follicle bulge stem cells while expanding the Lrig1(+) junctional zone and sebaceous glands. This was preceded first by a decrease in bone morphogenetic protein (BMP) and a subsequent increase in Wnt signaling. This imbalance in quiescent versus activating signals likely promoted a prolonged anagen-like hair follicle state after the second catagen, which exhausted stem cells over time ultimately resulting in hair loss in aged mice. K14-Cre-mediated deletion of CerS4 revealed a similar phenotype, thus suggesting an epidermis intrinsic function of CerS4 in regulating the regeneration of the pilosebaceous unit. The data indicate that CerS4-directed epidermal ceramide composition is essential to control hair follicle stem and progenitor cell behavior potentially through its regulation of BMP and Wnt signaling.
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Peters
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne, Germany; Department of Dermatology, University of Cologne, Cologne, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Vorhagen
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Brodesser
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Jakobshagen
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Cologne, Germany; Institute for Genetics, University of Cologne, Cologne, Germany; Center for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany; Max Planck Institute for Neurological Research, Cologne, Germany.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.affiliation: Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Cologne, Germany; Department of Dermatology, University of Cologne, Cologne, Germany. Electronic address: carien.niessen@uni-koeln.de.
authors.forename: Carien M
authors.initials: CM
authors.lastname: Niessen
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD), Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), Cologne, Germany. Electronic address: m.kroenke@uni-koeln.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D002518:Ceramides / Q000378:metabolism; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D018859:Hair Follicle / Q000378:metabolism*; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010641:Phenotype; D051049:Sphingosine N-Acyltransferase / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology*; D060449:Wnt Signaling Pathway
chemical_list: D019485:Bone Morphogenetic Proteins; D002518:Ceramides; C000599817:CERS4 protein, mouse; D051049:Sphingosine N-Acyltransferase