In Vivo Single-Cell Detection of Metabolic Oscillations in Stem Cells

•We used a noninvasive method to study epidermal stem cell metabolism in vivo•The circadian clock regulates intermediary metabolism in epidermal stem cells•A high NADH/NAD+ ratio, reflecting increased glycolysis, is found during the night•This high NADH/NAD+ ratio correlates with a higher proportion of stem cells in S phase

SummaryThrough the use of bulk measurements in metabolic organs, the circadian clock was shown to play roles in organismal energy homeostasis. However, the relationship between metabolic and circadian oscillations has not been studied in vivo at a single-cell level. Also, it is unknown whether the circadian clock controls metabolism in stem cells. We used a sensitive, noninvasive method to detect metabolic oscillations and circadian phase within epidermal stem cells in live mice at the single-cell level. We observe a higher NADH/NAD+ ratio, reflecting an increased glycolysis/oxidative phosphorylation ratio during the night compared to the day. Furthermore, we demonstrate that single-cell metabolic heterogeneity within the basal cell layer correlates with the circadian clock and that diurnal fluctuations in NADH/NAD+ ratio are Bmal1 dependent. Our data show that, in proliferating stem cells, the circadian clock coordinates activities of oxidative phosphorylation and glycolysis with DNA synthesis, perhaps as a protective mechanism against genotoxicity.

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