The circadian molecular clock creates epidermal stem cell heterogeneity

Abstract

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...

Day–night cycles and the sleep-promoting factor, Sleepless, affect stem cell activity in the Drosophila testis

“…Thus, these populations represent only a portion of all replicating cells in the organism, making their identification and purification from intact tissues quite an elaborate task. Mouse hair follicle stem cells contain an endogenous circadian clock, which orchestrates a global transcriptional response during the anagen (hair follicle growth) phase, inducing stem cell migration and mitotic activation (14). However, the question of whether hair follicle stem cells undergo mitotic divisions preferentially at certain times of the day has not been addressed.…”

“…Consistent with previous findings (32), we did not detect expression of the core circadian clock genes period and timeless in the testis niche or stem cells, which suggests that there is no intrinsic clock function in these cells. Interestingly, murine spermatogonial stem cells also lack cell-autonomous circadian clocks (33), which is in contrast to clock-containing hair follicle, hematopoietic, and intestinal stem cells (14,(34)(35)(36). It is possible that central or peripheral circadian clocks located in the brain, other tissues (2), or even other cells of the testes drive rhythms in the GSCs/CPCs, although the absence of mitotic rhythms in constant darkness argues against this possibility (Fig.…”

“…Behavioral factors and environmental influences are also known to affect the frequency of cell divisions, adjusting tissue homeostasis to the changing conditions inside and outside the organism (7). Twentyfour-hour rhythms of division have been documented in several mammalian tissues, reflecting dynamic activity in complex populations of dividing cells consisting of stem cells and their differentiating progeny (8)(9)(10)(11)(12)(13)(14)(15). Altered behavioral states, such as insufficient sleep, pregnancy, and physical exercise, induce mitotic activity in the brain and other stem cell-supported tissues (4, 7).…”

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

“…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.…”

Circadian Rhythms in Stem Cell Biology and Function

“…This mechanism is heavily conserved throughout evolution and allows organisms to adapt and to synchronize themselves to diurnal fl uctuations in their environment. Circadian rhythmicity can be seen in many different life forms, ranging from unicellular organisms, like cyanobacteria, to highly specialized and stem cell heterogeneity (Janich et al 2011 ), cell division (Matsuo et al 2003 ;Kowalska et al 2013 ;Feillet et al 2014 ;Nagoshi et al 2004 ;Yang et al 2009;Unsal-Kaçmaz et al 2005 ), damage induced regeneration (Janich et al 2013 ), immune progenitor cell migration and differentiation (Scheiermann et al 2013 ;Yu et al 2013 ) as reviewed by Steven Brown ( 2014 ).…”