A Circadian Rhythm in both Complement Cascade (ComC) Activation and Sphingosine-1-Phosphate (S1P) Levels in Human Peripheral Blood Supports a Role for the ComC\u2013S1P Axis in Circadian Changes in the Number of Stem Cells Circulating in Peripheral Blood

Marta Budkowska,Jarosław Woźniak,Mariusz Z. Ratajczak,Adrianna Wojtowicz,Zuzanna Marcinowska,Ewa Ostrycharz,Barbara Dołęgowska

doi:10.1007/s12015-018-9836-7

Abstract

The number of hematopoietic stem/progenitor cells (HSPCs) circulating in peripheral blood (PB) is regulated by a circadian rhythm, and more HSPCs circulate in PB in the morning hours than at night. Different mechanisms have been proposed that might regulate this process, including changes in tonus of β-adrenergic innervation of bone marrow (BM) tissue. Our group reported that in mice circadian changes in the number of HSPCs circulating in PB correlates with diurnal activation of the complement cascade (ComC) and that the mice deficient in C5 component of ComC (C5-KO mice) do not show circadian changes in the number of circulating HSPCs in PB. We also reported the existence of a gradient between PB and BM of a bioactive phosphosphingolipid, sphingosine-1-phosphate (S1P), which is a major PB chemottractant for BM-residing HSPCs. Based on these observations, we investigated activation of the ComC and the level of S1P in the PB of 66 healthy volunteers. We found that both ComC activation and the S1P level undergo changes in a circadian cycle. While the ComC becomes highly activated during deep sleep at 2 am, S1P becomes activated later, and its highest level is observed at 8 am, which precedes circadian egress of HSPCs from BM into PB. In sum, circadian activation of the ComC–S1P axis releases HSPCs from BM into PB.

Highlights

A day–night circadian rhythm is synchronized by a process that is coordinated by the pineal gland, which produces and releases melatonin into peripheral blood (PB) [1]
Our results provide evidence for circadian changes in activation of the complement cascade (ComC)–S1P axis, which, according to our hypothesis, drives circadian changes in the number of hematopoietic stem/progenitor cells (HSPCs) circulating in PB [25]
This observation has implications for circadian release or mobilization of HSPCs from bone marrow (BM) into PB, because activation of the ComC in the BM microenvironment is the driving force for release of these cells from their BM niches, and this occurs in the presence of an S1P gradient between BM and PB [25]

Summary

Introduction

A day–night (or light–dark) circadian rhythm (biological clock) is synchronized by a process that is coordinated by the pineal gland, which produces and releases melatonin into peripheral blood (PB) [1]. Melatonin is a well-defined biochemical coordinator of circadian rhythms [2,3,4,5]. Several biological processes in the body undergo circadian changes caused by i) the release of relevant hormones (e.g., the abovementioned melatonin and adrenal gland steroids), ii) the tonus in innervation of tissues by the sympathetic and parasympathetic autonomic nerve fibers, iii) the sleeping–waking rhythm, and iv) the effect of light on the organism [1, 6]. Perturbation of the normal circadian rhythm may lead to organ dysfunction, accelerated atherosclerosis, and even neoplasm [4].

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Conclusion