Daily light and darkness onset and circadian rhythms metabolically synchronize hematopoietic stem cell differentiation and maintenance: The role of bone marrow norepinephrine, tumor necrosis factor, and melatonin cycles

Abstract

Hematopoietic stem and progenitor cells (HSPCs) are essential for daily mature blood cell production, host immunity, and osteoclast-mediated bone turnover. The timing at which stem cells give rise to mature blood and immune cells while maintaining the bone marrow (BM) reservoir of undifferentiated HSPCs and how these opposite tasks are synchronized are poorly understood. Previous studies revealed that daily light onset activates norepinephrine (NE)-induced BM CXCL12 downregulation, followed by CXCR4 + HSPC release to the circulation. Recently, we reported that daily light onset induces transient elevations of BM NE and tumor necrosis factor (TNF), which metabolically program BM HSPC differentiation and recruitment to replenish the blood. In contrast, darkness onset induces lower elevations of BM NE and TNF, activating melatonin production, which metabolically reprograms HSPCs, increasing their short-and long-term repopulation potential, and BM maintenance. How the functions of BMretained HSPCs are influenced by daily light and darkness cycles and their clinical potential are further discussed.

Norepinephrine Inhibits the Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells via β2-Adrenoceptor-Mediated ERK1/2 and PKA Phosphorylation

“…The extensive proliferation capacity of BMSCs, which is a prerequisite for regeneration processes, depends on several bone marrow microenvironmental factors [9]. Although the presence of sympathetic nerve fibers and the release of the major sympathetic neurotransmitter NE in the human bone marrow and in the synovial fluid is well known [12,13,24], no studies analyzing the effect of NE on the proliferation capacity of human BMSCs have been performed until now. Therefore, our study aimed to investigate the effect of NE on the proliferation of human BMSCs.…”

“…The proliferation capacity of BMSCs is affected by numerous microenvironmental factors such as tissue origin, growth factors, oxygen concentration, presence of inflammatory mediators or hormones [9][10][11]. The bone marrow is innervated by sympathetic nerve fibers [12] and thus, the sympathetic nervous system may influence BMSCs proliferation. Sympathetic nerve fibers express tyrosine hydroxylase (TH), which is the key enzyme for the biosynthesis of catecholamines, such as e.g., norepinephrine (NE), one of the major peripheral sympathetic neurotransmitters.…”

“…Sympathetic nerve fibers express tyrosine hydroxylase (TH), which is the key enzyme for the biosynthesis of catecholamines, such as e.g., norepinephrine (NE), one of the major peripheral sympathetic neurotransmitters. NE is indeed present in the bone marrow in physiological concentrations (up to 10 −9 M) [12]. In addition, the synovial fluid of knee trauma and OA patients contains relevant NE concentrations, namely 10 −9 M to 10 −7 M, suggesting that BMSC proliferation might also be affected after migration from the bone marrow to the damaged cartilage area [13].…”

The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy

“…The promising profile of melatonin to treat COVID-19 is based on hindering several key steps for SARS-CoV-2 infectivity and the onset of disease, as well as on the improvement of respiratory and non-respiratory clinical features and the resynchronization of circadian disruption commonly found in affected individuals [10,87]. Specifically, nocturnal pineal melatonin is synchronized with an acute proliferation of hematopoietic stem and progenitor cells [88], and, accordingly, sleep deprivation led to disorders associated with chronic inflammatory tone. Therefore, we consider: (i) that the aged population represents the most vulnerable group to COVID-19 infection; (ii) the natural age-related decline of melatonin levels, (iii) that higher exposure of individuals to LAN also reduces melatonin levels and disrupts circadian rhythmicity.…”

Neurogenic Heterotopic Ossifications Recapitulate Hematopoietic Stem Cell Niche Development Within an Adult Osteogenic Muscle Environment

“…The close relationship between CNS, SNS, Parasympathetic Nervous System, bone metabolism and HSC migration, differentiation and self-renewal is illustrated by the important role of the circadian norepinephrine release by SNS nerves which triggers β3 AR and β2 AR expressed by BM mesenchymal cells and osteoblasts in both humans and mice (Golan et al, 2018(Golan et al, , 2019. Cholinergic signaling in the BM via neurons from both the PNS and SNS in tandem with adrenergic signaling derived from the SNS is also reported to contribute to regulate the circadian regulation of CXCL12 expression in the BM (García-García et al, 2019;García-García and Méndez-Ferrer, 2020).…”