title: β-Catenin Stabilization in Skin Fibroblasts Causes Fibrotic Lesions by Preventing Adipocyte Differentiation of the Reticular Dermis.
abstract: The Wnt/β-catenin pathway plays a central role in epidermal homeostasis and regeneration, but how it affects fibroblast fate decisions is unknown. We investigated the effect of targeted β-catenin stabilization in dermal fibroblasts. Comparative gene expression profiling of stem cell antigen 1(-) (Sca1(-)) and Sca1(+) neonatal fibroblasts from upper and lower dermis, respectively, confirmed that Sca1(+) cells had a preadipocyte signature and showed differential expression of Wnt/β-catenin-associated genes. By targeting all fibroblasts or selectively targeting Dlk1(+) lower dermal fibroblasts, we found that β-catenin stabilization between developmental stages E16.5 and P2 resulted in a reduction in the dermal adipocyte layer with a corresponding increase in dermal fibrosis and an altered hair cycle. The fibrotic phenotype correlated with a reduction in the potential of Sca1(+) fibroblasts to undergo adipogenic differentiation ex vivo. Our findings indicate that Wnt/β-catenin signaling controls adipogenic cell fate within the lower dermis, which potentially contributes to the pathogenesis of fibrotic skin diseases.
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Mastrogiannaki
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Beate M
authors.initials: BM
authors.lastname: Lichtenberger
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reimer
authors.affiliation: Wellcome Trust Centre for Stem Cell Research, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Collins
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Ryan R
authors.initials: RR
authors.lastname: Driskell
authors.affiliation: Centre for Stem Cells and Regenerative Medicine, King's College London, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK. Electronic address: fiona.watt@kcl.ac.uk.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005355:Fibrosis / Q000473:pathology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012871:Skin Diseases / Q000473:pathology* / Q000503:physiopathology; D060449:Wnt Signaling Pathway / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics*
chemical_list: D051176:beta Catenin