title: Thyroid hormone signaling controls hair follicle stem cell function.
abstract: Observations in thyroid patients and experimental animals show that the skin is an important target for the thyroid hormones. We previously showed that deletion in mice of the thyroid hormone nuclear receptors TRα1 and TRβ (the main thyroid hormone-binding isoforms) results in impaired epidermal proliferation, hair growth, and wound healing. Stem cells located at the bulges of the hair follicles are responsible for hair cycling and contribute to the regeneration of the new epidermis after wounding. Therefore a reduction in the number or function of the bulge stem cells could be responsible for this phenotype. Bulge cells show increased levels of epigenetic repressive marks, can retain bromodeoxyuridine labeling for a long time, and have colony-forming efficiency (CFE) in vitro. Here we demonstrate that mice lacking TRs do not have a decrease of the bulge stem cell population. Instead, they show an increase of label-retaining cells (LRCs) in the bulges and enhanced CFE in vitro. Reduced activation of stem cells leading to their accumulation in the bulges is indicated by a strongly reduced response to mobilization by 12-O-tetradecanolyphorbol-13-acetate. Altered function of the bulge stem cells is associated with aberrant activation of Smad signaling, leading to reduced nuclear accumulation of β-catenin, which is crucial for stem cell proliferation and mobilization. LRCs of TR-deficient mice also show increased levels of epigenetic repressive marks. We conclude that thyroid hormone signaling is an important determinant of the mobilization of stem cells out of their niche in the hair bulge. These findings correlate with skin defects observed in mice and alterations found in human thyroid disorders.
authors: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors: Constanza
authors: C
authors: Contreras-Jurado
authors: Molecular Oncology Unit, Division of Biomedicine, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, 28040 Madrid, Spain.
authors: Corina
authors: C
authors: Lorz
authors: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain.
authors: Laura
authors: L
authors: García-Serrano
authors: Molecular Oncology Unit, Division of Biomedicine, Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, 28040 Madrid, Spain jesusm.paramio@ciemat.es aaranda@iib.uam.es.
authors: Jesus M
authors: JM
authors: Paramio
authors: Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, 28029 Madrid, Spain jesusm.paramio@ciemat.es aaranda@iib.uam.es.
authors: Ana
authors: A
authors: Aranda
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D005260:Female; D017353:Gene Deletion; D018859:Hair Follicle / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D013963:Thyroid Hormones / Q000502:physiology*
chemical_list: D011988:Receptors, Thyroid Hormone; D051785:Smad Proteins; D013963:Thyroid Hormones
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