Circadian Rhythms in Stem Cell Biology and Function

Abstract

5.1 Introduction Terrestrial life revolves around the 24-h cycle of day and night. The light-dark cycle has a direct infl uence on organismal functioning, dictating wake-sleep patterns in animals and cycles of photosynthesis in plants. An underlying mechanism termed the circadian clock regulates these processes at the molecular level. The word circa-dian is derived from the two Latin words circa and dies which mean " around " and " day " respectively. 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 58 complex multicellular organisms, such as mammals. Concomitantly, circadian rhythms regulate many body features of animals like behavior, metabolism, blood pressure, body temperature, tissue physiology, regeneration and homeostasis (Aschoff 1983). The central core clock in mammals is located in the suprachiasmatic nucleus (SCN), a group of approximately 20,000 neurons in the anterior hypothalamus in the brain. The SCN clock is driven by light, the signal that is relayed after percep-tion in the retina by photoreceptors. However, the clock processes are not driven by light per se. Light should be seen as the main external synchronizer (also known as zeitgeber ; time-giver) forcing the body to adapt to a 24-h period, rather than driving circadian rhythmicity in physiology directly. The SCN synchronizes peripheral clocks through neural and humoral factors like the serotonin-derived hormone melatonin (Cajochen et al. 2003). Peripheral clocks are present in almost all tissues in the mammalian body, including liver, lung, kidney, skin, and the heart. These clocks maintain circadian tissue physiology via controlling tissue-specifi c gene expression (Brown and Azzi 2013). The molecular machinery behind this timekeeping system comprises multiple genes, termed clock genes , which products interact with each other ensuring stable and robust circadian rhythmicity. The hallmark of circadian rhythms is that they keep on cycling with the same phase in the absence of an external input. This can be seen by the persistence of circadian rhythmicity when animals are kept in complete darkness. Another typical feature of the circadian clock is the fact that it is not altered by external perturbation or at mild variations of ambient temperatures, a process known as " temperature compensation " (Merrow et al. 2005). This is nicely illustrated by the fact that the clocks of warm-blooded animals are buffered against and maintained at different temperatures throughout the day. The importance of maintaining a functional time-keeping system is shown by the fact that disruption of the clock has been associated with a vast array of malig-nancies, such as impairment of lipid homeostasis resulting in a fatty liver and obesity (Adamovich et al. 2014). A disturbed regulation of the clock has also been linked to the development of cardiovascular diseases, multiple sleep disorders, depression, infl ammation, cancer, impairment of regenerative capacity and other metabolic disorders (Rudic et al. 2004 ; Kennaway et al. 2013 ; Lumaban and Nelson 2014) like diabetes (Marcheva et al. 2010 ; Milagro et al. 2012). Furthermore, recent research has shown that circadian timekeeping can also be linked to developmental and physiological processes that are not necessarily asso-ciated with a 24-h daily pattern. This can be observed in clocks regulating somatic