The Autonomic Nervous System Pulls the Strings to Coordinate Circadian HSC Functions

Abstract

As for many other adult stem cells, the behavior of hematopoietic stem and progenitor cells (HSPCs) is subjected to circadian regulatory patterns. Multiple HSPC functions, such as proliferation, differentiation or trafficking exhibit time-dependent patterns that require a tight coordination to ensure daily blood cell production. The autonomic nervous system, together with circulating hormones, relay circadian signals from the central clock-the suprachiasmatic nucleus in the brain-to synchronize HSC niche physiology according to light/darkness cycles. Research over the last 20 years has revealed how specific neural signals modulate certain aspects of circadian HSC biology. However, only recently some studies have started to decipher the cellular and molecular mechanisms that orchestrate this complex regulation in a time-dependent fashion. Here we firstly review some of the recent key findings illustrating how different neural signals (catecholaminergic or cholinergic) regulate circadian HSC egress, homing, maintenance, proliferation, and differentiation. In particular, we highlight the critical role of different neurotransmitter receptors in the bone marrow microenvironment to channel these neural signals and regulate antagonistic processes according to circadian cues and organismal demands. Then, we discuss the potential biological meaning of HSC circadian regulation and its possible utility for clinical purposes. Finally, we offer our perspective on emerging concepts in HSC chronobiology.

The Brain: Is it a Next Frontier to Better Understand the Regulation and Control of Hematopoiesis for Future Modulation and Treatment?

“…In support of the brain/hematopoietic regulatory link hypothesis is some evidence that the nervous system has a role in regulating HSC, HPC, and hematopoiesis [30][31][32], and that dipeptidylpeptidase (DPP)4/CD26 [24,25,[33][34][35][36][37][38][39] is implicated in mobilization of HSC/HPC out from BM to the blood, and also for regulation of cytokine activity [39]. DPP4 can cleave the neurotransmitter Neuropeptide Y (NPY), and recent work has shown that manipulation of endothelial NPY and its receptors alters behavior of HSC and HPC [24,25].…”

“…These cells are important for maintaining/sustaining immunity and fighting cancer/leukemia and pre-cancer/leukemia cells. These mature cells, including platelets are produced by immature subsets of HSC and HPC found and nurtured mainly in BM of newborns and young and old adults through communication between cytokines, chemokines, and the microenvironment, as well as cell-cell interactions [12,13,[30][31][32]. HSC are functionally defined by their capacity to make more of themselves (self-renew) and to differentiate to form HPC and more mature cells.…”

The Circadian Clock and Viral Infections

“…Many factors can synchronize peripheral clocks, including the autonomic nervous system ( Becker et al, 2019 ; Garcia-Garcia and Mendez-Ferrer, 2020 ), body temperature ( Buhr et al, 2010 ), fasting/feeding cycles ( Wehrens et al, 2017 ; Lewis et al, 2020 ), and cytokines and hormones ( Astiz et al, 2019 ). The autonomic nervous system is influenced by the circadian clock, and some viruses can infect the peripheral and central nervous system ( Koyuncu et al, 2013 ); however, at the present time, there is no evidence for a direct interaction of viruses, clock, and the autonomic nervous system.…”

“…The influence of the SCN on the autonomic nervous system alters the sensitivity of peripheral tissues to hormones ( Buijs et al, 2006 ). Consequently, the same hormone stimulus may induce different responses dependent on the time of the day ( Becker et al, 2019 ; Garcia-Garcia and Mendez-Ferrer, 2020 ). The importance of the SCN as the main pacemaker becomes evident as transplantation of a functioning SCN reestablishes the circadian rhythm in genetically arrhythmic mice ( Ralph et al, 1990 ; Sujino et al, 2003 ); however, other extracellular cues can independently synchronize peripheral tissues.…”

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 , 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 ). Likewise, the CNS exerts long range regulation of HSCs.…”