Membran-Sphingolipid-Zusammensetzung und Ihre Rolle in der Aufrechterhaltung der Homöostase adulter Stammzellpopulationen

• Antragstellerin: Dr. Franziska Peters
• Fachliche Zuordnung: Dermatologie ; Kinder- und Jugendmedizin
• Förderung: Förderung von 2022 bis 2023
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 510221996

• Erstellungsjahr: 2024

Zusammenfassung der Projektergebnisse

Bioactive sphingolipids are vital membrane components, forming a selective barrier for subcellular compartmentalization and enabling cell type-specific intercellular communication by regulating plasma membrane receptors repertoires. The mechanisms behind achieving cell type-specific lipid compositions and their functional significance in tissue morphogenesis and maintenance have remained unclear. Here, we identify a specific role of ceramide synthase 4 (CerS4) in orchestrating fate decisions in hair follicle stem cells of the skin epidermis. Deletion of CerS4 hampers the development of the adult hair follicle bulge stem cell niche by altering hair follicle stem cell precursor differentiation trajectories towards upper hair follicle and inner bulge fates. Mechanistically, hair follicle stem cell differentiation defects originate from imbalanced ceramides and their derivative sphingolipids in hair follicle stem cells, linked with hyperactive canonical Wnt signaling. Impaired hair follicle stem cell niche establishment disrupts hair follicle architecture and barrier function. Cell-autonomous defects in hair follicle stem cell homeostasis induced by loss of CerS4 trigger a transcriptional RNA signature, a hair follicle stem cell-intrinsic protein expression profile and a Th2 dominated immune phenotype, that resembles features of human atopic dermatitis. This research reveals a fundamental role for a cell state-specific sphingolipid profile in the homeostasis of epidermal stem cells and, for the first time, associates dysregulation of sphingolipid metabolism with the development of a macroscopic, histologic and molecular phenotype resembling atopic dermatitis-like eczema.

Projektbezogene Publikationen (Auswahl)

• What doesn’t kill you makes you differentiate. Developmental Cell, 56(24), 3303-3304.
  Peters, Franziska & Wickström, Sara A.
  
• “Elucidating the role of sphingolipid metabolism in epidermal stem and progenitor cell dynamics”. (2022) Kick off meeting. Nuuksio. Finland. (Poster)
  Peters F., Biggs L. & Wickström S.A.
  
• “Sphingolipid metabolism orchestrates epidermal stem cell fate – potential insights into eczema initiation.” (2022) 3rd Interdisciplinary Networking Symposium for Clinicians and Medical Scientists – Else Kröner Symposium. Münster. Germany. (Talk)
  Peters F. & Wickström S.A.
  
• “Sphingolipid metabolism orchestrates epidermal stem cell state and fate – potential insights into eczema initiation.” (2023) Arbeitsgemeinschaft Dermatologische Forschung (ADF). Innsbruck. Austria (Poster and Talk)
  Peters F. & Wickström SA
  
• “Membrane sphingolipid composition orchestrating adult stem cell maintenance and fate” (V25). (2024) Allergology. 47:87-104.
  Peters F.
  
• “Sphingolipid metabolism orchestrates the establishment of the adult hair follicle stem cell niche to control skin homeostasis.” (2024) under Revision.
  Peters F., Brodesser S. Kruse K., Drexler H.C.A., Hu J., Lukas D., von Stebut-Borschitz E., Krönke M., Niessen C.M. & Wickström S.A.