title: Nfatc1 orchestrates aging in hair follicle stem cells.
abstract: Hair production is fueled by stem cells (SCs), which transition between cyclical bouts of rest and activity. Here, we explore why hair growth wanes with age. We show that aged hair follicle SCs (HFSCs) in mice exhibit enhanced resting and abbreviated growth phases and are delayed in response to tissue-regenerating cues. Aged HFSCs are poor at initiating proliferation and show diminished self-renewing capacity upon extensive use. Only modestly restored by parabiosis, these features are rooted in elevated cell-intrinsic sensitivity and local elevation in bone morphogenic protein (BMP) signaling. Transcriptional profiling presents differences consistent with defects in aged HFSC activation. Notably, BMP-/calcium-regulated, nuclear factor of activated T-cell c1 (NFATc1) in HFSCs becomes recalcitrant to its normal down-regulating cues, and NFATc1 ChIP-sequencing analyses reveal a marked enrichment of NFATc1 target genes within the age-related signature. Moreover, aged HFSCs display more youthful levels of hair regeneration when BMP and/or NFATc1 are inhibited. These results provide unique insights into how skin SCs age.
authors.affiliation: Laboratory of Mammalian Cell Biology and Development and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.
authors.forename: Brice E
authors.initials: BE
authors.lastname: Keyes
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Segal
authors.forename: Evan
authors.initials: E
authors.lastname: Heller
authors.forename: Wen-Hui
authors.initials: WH
authors.lastname: Lien
authors.forename: Chiung-Ying
authors.initials: CY
authors.lastname: Chang
authors.forename: Xingyi
authors.initials: X
authors.lastname: Guo
authors.forename: Dan S
authors.initials: DS
authors.lastname: Oristian
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D018859:Hair Follicle / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D015595:Skin Aging / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse
keywords: BMP signaling; hair cycle; quiescence