Circadian Clock Genes Contribute to the Regulation of Hair Follicle Cycling

Lin, Kevin K.; Kumar, Vivek; Geyfman, Mikhail; Chudova, Darya; Ihler, Alexander T.; Smyth, Padhraic; Paus, Ralf; Takahashi, Joseph S.; Andersen, Bogi

doi:10.1371/journal.pgen.1000573

Cited by 148 publications

(242 citation statements)

References 52 publications

(75 reference statements)

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“…22 The circadian genes may play a role in aging of the hair follicle which is manifested in hair loss and color. 23 TP53 can convert CDKN1A (p21 CIP1 )-induced irreversible senescence into reversible quiescence possibly by inhibiting the mechanistic target of rapamycin (MTOR).…”

Section: Resultsmentioning

confidence: 99%

Aging hair follicles rejuvenated by transplantation to a young subcutaneous environment

Cao

Kajiura

et al. 2016

Cell Cycle

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We demonstrate in the present study that young host mice rejuvenate aged hair follicles after transplantation. Young mice promote the hair shaft growth of transplanted old hair follicles, as well as young follicles, in contrast to old host mice, which did not support hair-shaft growth from transplanted old or young follicles. Nestin-expressing hair follicle-associated pluripotent (HAP) stem cells of transplanted old and young hair follicles remained active in young host nude mice. In contrast, the nestin-expressing HAP stem cells in young and old hair follicles transplanted to old nude mice were not as active as in young nude host mice. The present study shows that transplanted old hair follicles were rejuvenated by young host mice, suggesting that aging may be reversible.

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Section: Resultsmentioning

confidence: 99%

Aging hair follicles rejuvenated by transplantation to a young subcutaneous environment

Cao

Kajiura

et al. 2016

Cell Cycle

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“…6a, b). Deletion of Bmal1 causes circadian arrhythmicity without the need to perturb any other core circadian member 21 , and its ubiquitous deletion causes premature ageing, including defects in adult skin morphogenesis [25][26][27] . We crossed Bmal1KO and Per1-venus mice, and verified that the circadian clock of bulge stem cells and basal interfollicular epidermal cells was arrhythmic, and permanently skewed towards a clock low (venus dim ) state ( Supplementary Fig.…”

Section: Clock Arrhythmia Affects Homeostasismentioning

confidence: 99%

The circadian molecular clock creates epidermal stem cell heterogeneity

Janich

Pascual

Merlos‐Suárez

et al. 2011

Nature

279

290

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Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.Epidermal stem cells ensure that skin homeostasis is maintained. Murine epidermal stem cells are located either at the permanent portion of the hair follicle-termed the bulge-and are exclusively responsible for hair cycling [1][2][3][4] ; or at the junction between the epidermis and the hair follicle (isthmus), and feed into the epidermis and sebaceous glands [5][6][7] . In addition, a continuous proliferation of basal interfollicular epidermal cells ensures daily epidermal maintenance 8 .Bulge stem cells undergo bouts of activation followed by periods of dormancy, to establish hair follicle cycling. Robust TGF-b and Bmp signals act as 'activation breaks', rendering bulge cells dormant during the resting phase of the hair cycle (telogen) [9][10][11] . At the onset of the growth phase (anagen), bulge cells respond to Wnt signals by migrating into the lower proliferative hair germ region, where they contribute to follicle growth [12][13][14][15] . Subsequently, at mid-anagen, the bulge undergoes a second round of activation, which replenishes cells lost at the onset of anagen 2,3 . However, the response of bulge stem cells to activating stimuli is a heterogeneous process, as only a subset of them become active during either stage of activation 12,13 . The nature of such niche heterogeneity is currently unknown. Importantly, perturbing the equilibrium between the responsive and non-responsive stem cell states causes tissue malfunction and increases the risk of carcinogenesis [16][17][18][19][20] .Here, we analysed the role of the molecular clock in fine-tuning the function of epidermal stem cells. The mammalian clock machinery anticipates and synchronizes vital functions related to the physiological circadian needs of the organism 21 . The core molecular clock is established by a positive limb, composed of heterodimers of the transcription fa...

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“…Furthermore, hfSCs respond to body hormone status (3) and changes in circadian rhythms (16,17). Thus, hfSCs present a unique adult stem cell population for us to identify the essential property of a robust gene network capable of maintaining stem cell homeostasis while allowing plasticity to shift between a continuum of quiescent and activated states before becoming irreversibly committed.…”

mentioning

confidence: 99%

Competitive balance of intrabulge BMP/Wnt signaling reveals a robust gene network ruling stem cell homeostasis and cyclic activation

Kandyba

Leung

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

160

214

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Hair follicles facilitate the study of stem cell behavior because stem cells in progressive activation stages, ordered within the follicle architecture, are capable of cyclic regeneration. To study the gene network governing the homeostasis of hair bulge stem cells, we developed a Keratin 15-driven genetic model to directly perturb molecular signaling in the stem cells. We visualize the behavior of these modified stem cells, evaluating their hair-regenerating ability and profile their molecular expression. Bone morphogenetic protein (BMP)-inactivated stem cells exhibit molecular profiles resembling those of hair germs, yet still possess multipotentiality in vivo. These cells also exhibit up-regulation of Wnt7a, Wnt7b, and Wnt16 ligands and Frizzled (Fzd) 10 receptor. We demonstrate direct transcriptional modulation of the Wnt7a promoter. These results highlight a previously unknown intra-stem cell antagonistic competition, between BMP and Wnt signaling, to balance stem cell activity. Reduced BMP signaling and increased Wnt signaling tilts each stem cell toward a hair germ fate and, vice versa, based on a continuous scale dependent on the ratio of BMP/Wnt activity. This work reveals one more hierarchical layer regulating stem cell homeostasis beneath the stem cell-dermal papilla-based epithelial-mesenchymal interaction layer and the hair follicle-intradermal adipocyte-based tissue interaction layer. Although hierarchical layers are all based on BMP/Wnt signaling, the multilayered control ensures that all information is taken into consideration and allows hair stem cells to sum up the total activators/inhibitors involved in making the decision of activation.hair follicle stem cells | β-catenin | BMPR1A

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Circadian Clock Genes Contribute to the Regulation of Hair Follicle Cycling

Cited by 148 publications

References 52 publications

Aging hair follicles rejuvenated by transplantation to a young subcutaneous environment

Aging hair follicles rejuvenated by transplantation to a young subcutaneous environment

The circadian molecular clock creates epidermal stem cell heterogeneity

Competitive balance of intrabulge BMP/Wnt signaling reveals a robust gene network ruling stem cell homeostasis and cyclic activation

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