Human Epidermal Stem Cell Function Is Regulated by Circadian Oscillations

Abstract

Human skin copes with harmful environmental factors that are circadian in nature, yet how circadian rhythms modulate the function of human epidermal stem cells is mostly unknown. Here we show that in human epidermal stem cells and their differentiated counterparts, core clock genes peak in a successive and phased manner, establishing distinct temporal intervals during the 24 hr day period. Each of these successive clock waves is associated with a peak in the expression of subsets of transcripts that temporally segregate the predisposition of epidermal stem cells to respond to cues that regulate their proliferation or differentiation, such as TGFβ and calcium. Accordingly, circadian arrhythmia profoundly affects stem cell function in culture and in vivo. We hypothesize that this intricate mechanism ensures homeostasis by providing epidermal stem cells with environmentally relevant temporal functional cues during the course of the day and that its perturbation may contribute to aging and carcinogenesis.

Circadian clock-mediated control of stem cell division and differentiation: beyond night and day

“…Consistent with the possible importance of this regulation, clock protein misexpression and/or a lack of circadian control has been documented in multiple tumor types (Hwang-Verslues et al, 2013; Luo et al, 2012;Zhao et al, 2013) and immortalized cell lines (Yeom et al, 2010). In normal physiology, circadian cell division has been documented in adult hippocampal neurogenesis (BouchardCannon et al, 2013), in intestinal and skin epithelial cell division (Geyfman et al, 2012;Janich et al, 2013;Karpowicz et al, 2013), and in multiple immune cell populations (Fortier et al, 2011;Keller et al, 2009) -essentially anywhere that cell division occurs in adult animals.…”

“…Given the importance of juxtacrine signaling during development, this heterogeneity might be important for optimizing cell fate decisions or could simply permit a broad population of cells expressing different receptors to respond to different cues at different times. In a subsequent study (Janich et al, 2013), the authors demonstrated the second possibility in vitro by showing that cultured and clock-synchronized keratinocyte stem cells responded better to certain differentiation cues at some times of day than at others. Consistent with their hypothesis, cells expressed different proliferation and differentiation pathway genes at different times of day.…”

“…Indeed, based on their gene expression data, the authors were able to distinguish 'functional intervals' during the stem cell differentiation process, in which activities of particular signaling pathways displayed maximum expression. In turn, clock genes themselves displayed ordered patterns of expression across these functional intervals, raising the possibility that circadian control might be necessary to achieve temporal orchestration of keratinocyte stem cell development within time windows even shorter than simply day and night (Janich et al, 2013). Further experiments using clock-deficient cells will no doubt shed further light upon this interesting hypothesis.…”

Circadian Rhythms in Stem Cell Biology and Function

“…In addition, the phase of circadian rhythms seems to play a role in differentiation. In human epidermal stem cells the phase of circadian rhythms determines proliferation predisposition (Janich et al 2013 ). When differentiation is induced by TGFβ or calcium, the core clock gene phase determines whether the epidermal stem cells respond to these cues.…”

“…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 ).…”