The circadian molecular clock creates epidermal stem cell heterogeneity

• Published in: Nature (London) 2011-12, Vol.480 (7376), p.209-214
• Main Authors: Janich, Peggy, Pascual, Gloria, Merlos-Suárez, Anna, Batlle, Eduard, Ripperger, Jürgen, Albrecht, Urs, Cheng, Hai-Ying M., Obrietan, Karl, Di Croce, Luciano, Benitah, Salvador Aznar
• Format: Article
• Language: English
• Subjects: 631/136/532; 631/443/319/1557; 631/80/105; 692/699/67; Animals; ARNTL Transcription Factors - deficiency; ARNTL Transcription Factors - genetics; ARNTL Transcription Factors - metabolism; Artificial chromosomes; Binding sites; Biological and medical sciences; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Adhesion - genetics; Cell Cycle - genetics; Cells, Cultured; Cellular Senescence; Circadian Clocks - genetics; Circadian Clocks - physiology; Circadian Rhythm - genetics; Circadian Rhythm - physiology; Circadian rhythms; Cloning; Cues; Epidermis; Female; Gene Expression Regulation - genetics; Hair Follicle - cytology; Heterogeneity; Homeostasis; Homeostasis - genetics; Homeostasis - physiology; Humanities and Social Sciences; Male; Medical sciences; Mice; Mice, Knockout; multidisciplinary; Observations; Physiological aspects; Rodents; Science; Science (multidisciplinary); Skin Neoplasms - genetics; Skin Neoplasms - pathology; Stem Cell Niche; Stem cells; Stem Cells - cytology; Stem Cells - metabolism; Transforming Growth Factor beta - genetics; Tumors; Wnt Signaling Pathway - genetics
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature10649

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. The circadian clock fine-tunes the activation state of epidermal stem cells by regulating their ability to respond to their microenvironment; perturbation of this clock affects long-term tissue homeostasis and predisposition to tumorigenesis. Stem cells go by the clock Epidermal stem cells residing in specific niches in mouse skin ensure that skin homeostasis is efficiently maintained. Hair follicle bulge stem cells are responsible for hair follicle regeneration and wound healing. They produce a heterogeneous population of cells, for example in their ability to respond to intrinsic and extrinsic cues. This study by Salvador Benitah and colleagues shows that the circadian clock controls the activation state and the heterogeneity of bulge stem cells by regulating their ability to respond to their microenvironment. This means that a population of 'ready-to-go' cells is always available to respond to activation stimuli, while preventing all stem cells within the niche from becoming responsive. Perturbation of the epidermal stem-cell clock affects long-term tissue homeostasis and predisposition to tumorigenesis.