A desmosomal cadherin controls multipotent hair follicle stem cell quiescence and orchestrates regeneration through adhesion signaling
William V.J. Hariton,
Katja Schulze,
Siavash Rahimi,
Taravat Shojaeian,
Laurence Feldmeyer,
Roman Schwob,
Andrew M. Overmiller,
Beyza S. Sayar,
Luca Borradori,
Mỹ G. Mahoney,
Arnaud Galichet,
Eliane J. Müller
Affiliations
William V.J. Hariton
Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Department for BioMedical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Bern, Switzerland; DermFocus, Vetsuisse Faculty, University of Bern, 3008 Bern, Switzerland; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Katja Schulze
DermFocus, Vetsuisse Faculty, University of Bern, 3008 Bern, Switzerland; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Siavash Rahimi
Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Department for BioMedical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Bern, Switzerland; DermFocus, Vetsuisse Faculty, University of Bern, 3008 Bern, Switzerland
Taravat Shojaeian
Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Department for BioMedical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Bern, Switzerland; DermFocus, Vetsuisse Faculty, University of Bern, 3008 Bern, Switzerland
Laurence Feldmeyer
Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
Roman Schwob
DermFocus, Vetsuisse Faculty, University of Bern, 3008 Bern, Switzerland; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Andrew M. Overmiller
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Beyza S. Sayar
Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Department for BioMedical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Bern, Switzerland; DermFocus, Vetsuisse Faculty, University of Bern, 3008 Bern, Switzerland
Luca Borradori
Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; DermFocus, Vetsuisse Faculty, University of Bern, 3008 Bern, Switzerland
Mỹ G. Mahoney
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Arnaud Galichet
Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Department for BioMedical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Bern, Switzerland; DermFocus, Vetsuisse Faculty, University of Bern, 3008 Bern, Switzerland; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Eliane J. Müller
Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; Department for BioMedical Research, Molecular Dermatology and Stem Cell Research, University of Bern, 3008 Bern, Switzerland; DermFocus, Vetsuisse Faculty, University of Bern, 3008 Bern, Switzerland; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; Corresponding author
Summary: Stem cells (SCs) are critical to maintain tissue homeostasis. However, it is currently not known whether signaling through cell junctions protects quiescent epithelial SC reservoirs from depletion during disease-inflicted damage. Using the autoimmune model disease pemphigus vulgaris (PV), this study reveals an unprecedented role for a desmosomal cadherin in governing SC quiescence and regeneration through adhesion signaling in the multipotent mouse hair follicle compartment known as the bulge. Autoantibody-mediated, mechanical uncoupling of desmoglein (Dsg) 3 transadhesion activates quiescent bulge SC which lose their multipotency and stemness, become actively cycling, and finally delaminate from their epithelial niche. This then initiates a self-organized regenerative program which restores Dsg3 function and bulge morphology including SC quiescence and multipotency. These profound changes are triggered by the sole loss of functional Dsg3, resemble major signaling events in Dsg3−/− mice, and are driven by SC-relevant EGFR activation and Wnt modulation requiring longitudinal repression of Hedgehog signaling.
