Adult stem cell maintenance and tissue regeneration around the clock: do impaired stem cell clocks drive age-associated tissue degeneration?

Human adult stem cell research is a highly prolific area in modern tissue engineering as these cells have significant potential to provide future cellular therapies for the world's increasingly aged population. Cellular therapies require a smart biomaterial to deliver and localise the cell population; protecting and guiding the stem cells toward predetermined lineage-specific pathways. The cells, in turn, can provide protection to biomaterials and increase its longevity. The right combination of stem cells and biomaterials can significantly increase the therapeutic efficacy. Adult stem cells are utilised to target many changes that negatively impact tissue functions with age. Understanding the underlying mechanisms that lead to changes brought about by the ageing process is imperative as ageing leads to many detrimental effects on stem cell activation, maintenance and differentiation. The circadian clock is an evolutionarily conserved timing mechanism that coordinates physiology, metabolism and behavior with the 24 h solar day to provide temporal tissue homeostasis with the external environment. Circadian rhythms deteriorate with age at both the behavioural and molecular levels, leading to age-associated changes in downstream rhythmic tissue physiology in humans and rodent models. In this review, we highlight recent advances in our knowledge of the role of circadian clocks in adult stem cell maintenance, driven by both cell-autonomous and tissue-specific factors, and the mechanisms by which they co-opt various cellular signaling pathways to impose temporal control on stem cell function. Future research investigating pharmacological and lifestyle interventions by which circadian rhythms within adult stem niches can be manipulated will provide avenues for temporally guided cellular therapies and smart biomaterials to ameliorate age-related tissue deterioration and reduce the burden of chronic disease.