Abstract
Many of the components that regulate the circadian clock have been identified in organisms and humans. The influence of circadian rhythm (CR) on the regulation of stem cells biology began to be evaluated. However, little is known on the role of CR on human mesenchymal stem cell (hMSCs) properties. The objective of this study was to investigate the influence of CR on the differentiation capacities of bone marrow hMSCs, as well as the regulation of cell cycle and migration capabilities. To that, we used both a chemical approach with a GSK-3β specific inhibitor (2’E,3’Z-6-bromoindirubin-3’-oxime, BIO) and a knockdown of CLOCK and PER2, two of the main genes involved in CR regulation. In these experimental conditions, a dramatic inhibition of adipocyte differentiation was observed, while osteoblastic differentiation capacities were not modified. In addition, cell migration was decreased in PER2-/- cells. Lastly, downregulation of circadian clock genes induced a modification of the hMSCs cell cycle phase distribution, which was shown to be related to a change of the cyclin expression profile. Taken together, these data showed that CR plays a role in the regulation of hMSCs differentiation and division, and likely represent key factor in maintaining hMSCs properties.
Highlights
Circadian rhythms (CR) allow organizations to adapt to the periodic nature of the environment and anticipate the external light-dark cycle [1]
The relative expression of CLOCK, BMAL1, PER1, PER2, PPARγ, OSTEOCALCINE and GSK3β genes and CLOCK, BMAL1, PER1 and PER2 proteins was studied in individual cultures of Bone marrow (BM) human mesenchymal stem cell (hMSCs) (n = 3)
Rhythmicity was observed for all clock genes, with a period of oscillation (P) of 24 hours for CLOCK, BMAL1 and PER1, and 18 hours for PER2
Summary
Circadian rhythms (CR) allow organizations to adapt to the periodic nature of the environment and anticipate the external light-dark cycle [1]. These endogenous lilting allow the regulation of physiological processes such as glucose homeostasis [2] and cell cycle [3]. The circadian clock is intimately involved in the control of metabolic and physiological process and disruption can be either the cause or the effect of various disorders including metabolic syndrome [4] or cancer predisposition [5]. The circadian system in mammals is a complex hierarchical system organized around a set of neurons coupled at the suprachiasmatic nuclei (SCN) responsive to stimuli through the retinohypthalamic tract. In addition to the SCN, PLOS ONE | DOI:10.1371/journal.pone.0146674 January 7, 2016
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