Dual cholinergic signals regulate daily migration of hematopoietic stem cells and leukocytes

• Published in: Blood 2019-01, Vol.133 (3), p.224-236
• Main Authors: García-García, Andrés, Korn, Claudia, García-Fernández, María, Domingues, Olivia, Villadiego, Javier, Martín-Pérez, Daniel, Isern, Joan, Bejarano-García, José A., Zimmer, Jacques, Pérez-Simón, José A., Toledo-Aral, Juan J., Michel, Tatiana, Airaksinen, Matti S., Méndez-Ferrer, Simón
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; Bone Marrow Cells - physiology; Cell Adhesion; Cell Movement; Cells, Cultured; Chemotaxis; Cholinergic Agents - pharmacology; Circadian Rhythm; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Female; Glial Cell Line-Derived Neurotrophic Factor Receptors - physiology; Hematopoiesis and Stem Cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - physiology; Leukocytes - cytology; Leukocytes - drug effects; Leukocytes - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Parasympathetic Nervous System - physiology; Receptors, Adrenergic, beta-2; Receptors, Adrenergic, beta-3 - physiology; Receptors, G-Protein-Coupled - physiology; Sympathetic Nervous System - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2018-08-867648

Hematopoietic stem and progenitor cells (HSPCs) and leukocytes circulate between the bone marrow (BM) and peripheral blood following circadian oscillations. Autonomic sympathetic noradrenergic signals have been shown to regulate HSPC and leukocyte trafficking, but the role of the cholinergic branch has remained unexplored. We have investigated the role of the cholinergic nervous system in the regulation of day/night traffic of HSPCs and leukocytes in mice. We show here that the autonomic cholinergic nervous system (including parasympathetic and sympathetic) dually regulates daily migration of HSPCs and leukocytes. At night, central parasympathetic cholinergic signals dampen sympathetic noradrenergic tone and decrease BM egress of HSPCs and leukocytes. However, during the daytime, derepressed sympathetic noradrenergic activity causes predominant BM egress of HSPCs and leukocytes via β3–adrenergic receptor. This egress is locally supported by light-triggered sympathetic cholinergic activity, which inhibits BM vascular cell adhesion and homing. In summary, central (parasympathetic) and local (sympathetic) cholinergic signals regulate day/night oscillations of circulating HSPCs and leukocytes. This study shows how both branches of the autonomic nervous system cooperate to orchestrate daily traffic of HSPCs and leukocytes. •Central parasympathetic signals repress sympathetic tone at night to orchestrate day/night HSPC traffic.•Local sympathetic cholinergic signals modulate HSPC traffic by inhibiting diurnal BM vascular adhesion and β3-adrenergic signaling at night. [Display omitted]