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

Abstract

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.

Keywords: Adult stem cells; Aging; Circadian rhythms; Differentiation; Mechanical stimulation; Proliferation.

Fig. 1

Stem Cell Division. a Adult stem cells are capable of dividing either symmetrically, to produce two identical stem cells or two identical daughter cells, or asymmetrically, to produce one identical stem cell and one committed daughter cell. b The hierarchy of stem cell division

Fig. 2

The circadian system organisation and the molecular clock. Light enters the retina via photoreceptor cells and is transduced to the ‘master pacemaker’, the suprachiasmatic nucleus (SCN), in the anterior hypothalamus of the brain. The SCN relays signals to the ‘peripheral tissue clocks’ throughout the body. At a molecular level, circadian clocks are regulated via primary and stabilising feedback loops, which regulate core clock genes within each loop and numerous target genes in each tissue (clock-controlled genes, CCGs), leading to synchronisation of tissue-specific cellular functions (modified from Rogers et al. (2018) with persmission from BioMedicine)

Fig. 3

Summary of the Common Changes seen with Ageing and Circadian Clock Disruption