SCA1 + Cells from the Heart Possess a Molecular Circadian Clock and Display Circadian Oscillations in Cellular Functions

Abstract

SummaryStem cell antigen 1-positive (SCA1+) cells (SPCs) have been investigated in cell-based cardiac repair and pharmacological research, although improved cardiac function after injection has been variable and the mode of action remains unclear. Circadian (24-hr) rhythms are biorhythms regulated by molecular clocks that play an important role in (patho)physiology. Here, we describe (1) the presence of a molecular circadian clock in SPCs and (2) circadian rhythmicity in SPC function. We isolated SPCs from human fetal heart and found that these cells possess a molecular clock based on typical oscillations in core clock components BMAL1 and CRY1. Functional analyses revealed that circadian rhythmicity also governs SPC proliferation, stress tolerance, and growth factor release, with large differences between peaks and troughs. We conclude that SPCs contain a circadian molecular clock that controls crucial cellular functions. Taking circadian rhythms into account may improve reproducibility and outcome of research and therapies using SPCs.

Circadian clocks: from stem cells to tissue homeostasis and regeneration

“…We now know that this is not restricted to in vitro ES cell‐derived cardiac cultures as neonatal rat cardiomyocytes 84 and SCA1 + stem cells derived from human hearts 85 also show an oscillatory response to external stressors. Next to that, human SCA1 + cardiac stem cells showed circadian rhythmicity in proliferation and the secretion of a number of paracrine factors, such as β‐nerve growth factor (bNGF), stem cell factor (SCF), human placental growth factor (PGIF‐1), and vascular endothelial growth factor A (VEGF‐A) 85, was found to be rhythmic as well.…”

“…Next to that, human SCA1 + cardiac stem cells showed circadian rhythmicity in proliferation and the secretion of a number of paracrine factors, such as β‐nerve growth factor (bNGF), stem cell factor (SCF), human placental growth factor (PGIF‐1), and vascular endothelial growth factor A (VEGF‐A) 85, was found to be rhythmic as well. Strikingly, VEGF‐A, a well‐known growth factor involved in angiogenesis, also oscillated in human ES cell‐derived cardiomyocytes 53 and murine hearts 3.…”

Influence of mental stress and environmental toxins on circadian clocks: Implications for redox regulation of the heart and cardioprotection

“…Chronotherapy, sleep therapy, light therapy and melatonin administration can improve clinical outcomes after a cardiovascular event in both human and animal models have been conflicting (Lochner et al, 2013). Melatonin administered to AMI patients-independent of clock time-showed no improvement between left ventricular volumes, ejection fraction and infarct size compared to placebo (Dominguez-Rodriguez et al, 2017). On the other hand, more time-targeted therapy may have given different results and treating individuals with dysregulated circadian rhythms due to depression, jet lag and sleep disorders can reregulate circadian rhythms to help prevent the development of cardiovascular events (Srinivasan, Spence, Pandi-Perumal, Trakht, & Cardinali, 2008).…”

“…Our group found oscillating clock genes in human fetal and adult cardiac progenitor cells. Circadian rhythmicity influenced their ability to proliferate, tolerate different stressors, and secrete paracrine factors (Du Pre et al, 2017). Finally, normal vascular function in the heart is dependent on the circadian clock.…”

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

“…Furthermore, a number of clock-controlled output genes in the heart have been identified as an oscillatory network of stress-related genes, including genes known to play an important role in human heart physiology, including Pln , Kcne4 , Tspo , Cav1 and Rgs2 (Dierickx et al 2017 ). Stem cell antigen 1-positive (SCA1+) cells, which can be detected in the heart, have been shown to possess a molecular clock and exhibit circadian oscillations that control downstream cellular functions (Du Pré et al 2017 ). These findings demonstrate the importance of circadian regulation in cardiovascular functions.…”