Stem cells

The clock within

The molecular clock machinery regulates organisms' responses to daily variations in the environment. One unexpected response seems to be temporal fine-tuning of stem-cell behaviour in the skin. See Article p.209

In general, the physiology and behaviour of most organisms follow a daily, or circadian, rhythm. This contributes to adaptations to environmental variables such as the light–dark cycle. Although in mammals the coherent ticking of circadian oscillations is ultimately orchestrated by a tiny region of the brain — the suprachiasmatic nucleus1 — the oscillations are intrinsic to almost all tissues and cells, including the epidermal layers of the skin. Circadian oscillations in gene expression are controlled by a number of factors that constitute the molecular clock. Strikingly, in the epidermis this molecular clock is not solely dedicated to the regulation of the tissue's circadian rhythms. On page 209 of this issue, Janich et al.2 report that the clock also controls the alternate cycles of dormancy and proliferation in mouse epidermal stem-cell populations. This finding places the molecular clock in a strategic position for the fine-tuning of epidermal homeostasis.

Adult stem cells are present in various organs and tissues, where they reside in distinct areas within specialized microenvironments, or 'niches'. They remain in a slow-cycling state until needed for the maintenance of tissue homeostasis. However, they can also become active in response to malignant signals, leading to inflammation and cancer. The transition of stem cells from dormancy to proliferation remains poorly understood. One question is why only a few stem cells of a population respond to proliferation and differentiation signals. Janich and colleagues provide unanticipated insight into this aspect of stem-cell biology.

The molecular machinery controlling circadian functions involves a complex network of auto-regulatory feedback loops that affect gene expression. The positive components of this machinery — the transcriptional activators CLOCK and BMAL1 — drive rhythmic expression of the clock-controlled genes. Among these are the genes that encode the negative components of the molecular clock, the repressor proteins cryptochrome (CRY1 and 2) and period (PER1–3)3. Additional factors, such as other clock-related proteins, post-translational modifications and small molecules that can feed back into the clock, add further complexity to the system, thereby ensuring regulated expression of at least 10% of the cellular genes in a circadian manner3.

Janich et al.2 studied a mouse model engineered to express a fluorescent protein in a way that reflects circadian clock oscillations. The authors find that, in the hair-follicle bulge (one of the two locations where epidermal stem cells reside), two subpopulations of stem cells coexist. These differ in the way that they express the core components of the clock machinery (Fig. 1). This, in turn, results in differential expression of several genes known to control stem-cell dormancy, proliferation and differentiation. Among these are genes that encode TGF-β factors, which inhibit proliferation and differentiation, and Wnt-signalling factors, which promote growth. Consequently, at any one time, one subpopulation is more prone to proliferation and differentiation.

Figure 1: Stem cells and circadian oscillations.

Epidermal stem cells coexist as two subpopulations: one that remains dormant and the other that becomes active to maintain epidermal homeostasis. Janich et al.2 report that, in response to circadian oscillations, the two subpopulations differentially express components of the clock machinery. This, in turn, affects expression of proteins such as Wnt signalling factors, which promote proliferation, and TGF-β factors, which inhibit growth. Other factors such as metabolites and hormones could also be involved in regulating epidermal stem-cell heterogeneity. The 'decision-making' processes probably involve metabolic and epigenetic control. Whether activated stem cells can become dormant again remains unknown.

What could be the advantage of two stem-cell subpopulations coexisting in the same niche? Stem-cell heterogeneity may have evolved to allow the cells both to self renew, thus replenishing their reserve in the niche, and to keep a ready-to-go population that can respond to the signals that trigger differentiation. Whether the two epidermal stem-cell subpopulations represent two lineages with distinct developmental origins, and whether they can interconvert, should be determined (Fig. 1).

In subsequent experiments, Janich and co-workers disrupted circadian rhythm in mice by selectively deleting the Bmal1 gene in the basal keratinocyte cells of the animals' skin. The hair-follicle bulges of these mice contained fewer proliferative cells and a higher number of dormant stem cells than those of normal mice. Moreover, Bmal1-deficient bulge stem cells were more responsive to TGF-β signalling and exhibited decreased expression of Wnt-related genes while maintaining higher expression levels of TGF-β-related genes. When the authors deleted the clock inhibitors Per1 and Per2, they observed the opposite effect — increased proliferation of bulge stem cells. Thus, the positive and negative components of the clock machinery seem to function as alternative rheostats of epidermal stem-cell proliferation.

Previous studies have also suggested a role for the circadian clock in stem-cell biology. For example, the release of haematopoietic stem cells — which develop into blood cells — from the bone marrow into the bloodstream follows a cyclical pattern that seems to be regulated by the circadian clock through the sympathetic nervous system4.

Adult stem-cell differentiation, which is essential for tissue homeostasis, has also been linked to circadian oscillations. Clock genes, for instance, mediate inhibition of bone formation from osteoblast cells, and several mouse models deficient in clock genes exhibit increased bone mass relative to controls5. Moreover, embryonic fibroblasts derived from mice lacking either Bmal1 or Per2 show altered ability to differentiate into adipocytes6,7, indicating that the clock machinery affects formation of the fat tissue. Janich et al. also find that disruption of Bmal1 in the skin of mice induces epidermal ageing and reduces tumorigenesis. These pieces of evidence clearly point to a role for the clock in maintaining skin-tissue homeostasis.

Janich and co-authors' findings2 consolidate the existing idea of crosstalk between circadian rhythms and differentiation. They also raise several questions. The undifferentiated state of the cell has been correlated with a lack of circadian physiology8. It is therefore important to determine which stimuli initiate the clock's ticking in the niche. It could be that, whereas differentiating stimuli can mediate this process in embryonic stem cells8, signals originating from the central nervous system activate adult stem cells. Other unknowns include how and when communication between the central pacemaker in the suprachiasmatic nucleus and the peripheral clocks it synchronizes is established, and how relevant it is to the differentiation process.

An emerging theme is that the metabolic state of cells is crucial for clock regulation and that the clock machinery contributes to the maintenance of the metabolic state. Indeed, the finding that the metabolic mediator NAD+ and its biosynthetic pathway are components of the circadian oscillatory network9,10 is evidence for modulation of the clock machinery through metabolic pathways. Because stem-cell metabolism is reprogrammed in response to differentiation signals11, the possibility that cyclical metabolism may contribute to epidermal stem-cell physiology is intriguing. Deciphering the relationship between circadian oscillations and stem-cell metabolism could lead to new targets to manipulate the differentiation and function of adult stem cells for regenerative medicine.

The information conveyed by differentiation signals is integrated into stem cells epigenetically — through chemical modifications of the genome that do not affect the DNA sequence but are inherited after cell division — to establish the cells' fate. Does the clock machinery contribute to this process? Accumulating evidence indicates that intricate chromatin (DNA–protein complexes) remodelling events that are involved in the establishment of several epigenetic marks in the genome follow a circadian pattern, and ultimately control circadian gene expression12. Establishment of such a clock-regulated epigenome during differentiation raises the attractive possibility that differentiating cells use the clock machinery to direct the epigenetic marks that define certain gene-transcription patterns in the new cell type. The existence of these fascinating links should become clear, as epigenetic features of epidermal stem cells are already being explored13,14.

This paper2 raises yet another intriguing question: is this mechanism of clock-mediated epidermal stem-cell control conserved in other adult stem cells? Expect exciting insight into stem-cell biology in the light of Janich and co-workers' data.


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Correspondence to Paolo Sassone-Corsi.

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Aguilar-Arnal, L., Sassone-Corsi, P. The clock within. Nature 480, 185–187 (2011).

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