Daily Onset of Light and Darkness Differentially Controls Hematopoietic Stem Cell Differentiation and Maintenance

Abstract

Hematopoietic stem and progenitor cells (HSPCs) tightly couple maintenance of the bone marrow (BM) reservoir, including undifferentiated long-term repopulating hematopoietic stem cells (LT-HSCs), with intensive daily production of mature leukocytes and blood replenishment. We found two daily peaks of BM HSPC activity that are initiated by onset of light and darkness providing this coupling. Both peaks follow transient elevation of BM norepinephrine and TNF secretion, which temporarily increase HSPC reactive oxygen species (ROS) levels. Light-induced norepinephrine and TNF secretion augments HSPC differentiation and increases vascular permeability to replenish the blood. In contrast, darkness-induced TNF increases melatonin secretion to drive renewal of HSPCs and LT-HSC potential through modulating surface CD150 and c-Kit expression, increasing COX-2/αSMA macrophages, diminishing vascular permeability, and reducing HSPC ROS levels. These findings reveal that light- and darkness-induced daily bursts of norepinephrine, TNF, and melatonin within the BM are essential for synchronized mature blood cell production and HSPC pool repopulation.

Novel Evidence that Purinergic Signaling - Nlrp3 Inflammasome Axis Regulates Circadian Rhythm of Hematopoietic Stem/Progenitor Cells Circulation in Peripheral Blood

“…The circadian changes in the number of circulating HSPCs in PB were the subject of several excellent studies showing a peak in the early morning hours and a nadir at night [5][6][7][8][9][10][11][12][13]. This phenomenon has been attributed to diurnal changes in tonus of the vegetative nerves that innervate BM tissue as a result of external light and dark cycles [4,9,10].…”

“…Recently, another group has demonstrated that lightinduced norepinephrine and TNF secretion augments HSPC differentiation and increases vascular permeability, which releases HSPCs into PB in a circadian rhythm-dependent manner [6]. At the same time, darkness-induced TNF increases melatonin secretion, which drives renewal of HSPCs and diminishes vascular permeability.…”

“…*p ≤ 0.05. All parameters studied in this work were measured at predefined ZT points only that daily light-and darkness-induced bursts of norepinephrine, TNF, and melatonin within the BM microenvironment are essential for synchronized diurnal release of HSPCs into PB [6]. Our team reported that activation and crosstalk between the complement cascade (ComC), the coagulation cascade (CoaC), and the fibrinolytic cascade (FibC) is essential for circadian release of HSPCs from BM into PB, as all these proteolytic cascades show circadian activation late at night or in the early morning hours due to deep-sleep hypoxia [7,12,13].…”

“…Circadian rhythms are internal processes that regulate the sleepwake cycle and repeat every 24 h. These processes are driven by a circadian clock and have been evolutionarily established in plants, fungi, bacteria, and animals, including mice and humans [1][2][3][4][5]. It is well known that this intrinsic circadian clock regulates all aspects of diurnal behavior and physiology, which includes melatonin secretion by the pineal gland, body temperature, and the plasma level of cortisol in mammals [5][6][7][8].…”

“…The number of circulating hematopoietic stem/progenitor cells (HSPCs) in peripheral blood (PB) follows a circadian rhythm pattern, with the peak occurring in the early morning hours and the nadir at night [3,6,9,10]. In an elegant paper it was demonstrated that the timing of this peak can be explained by fluctuations in the tonus of the vegetative nervous system [4].…”