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

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.
This work was supported by core support grants from the Wellcome Trust and the Medical Research Council (MRC) to the Cambridge Stem Cell Institute, the Spanish Ministry of Economy and Competitiveness (SAF-2011-30308), the Pro-CNIC Foundation, Severo Ochoa Center of Excellence award SEV-2015-0505 to CNIC, Ramón y Cajal Program grant RYC-2009-04703, Marie Curie Career Integration grant FP7-PEOPLE-2011-RG-294096, ConSEPOC-Comunidad de Madrid S2010/BMD-2542, Red TerCel (Instituto de Salud Carlos III (ISCIII)-Spanish Cell Therapy Network), National Health Institute Blood and Transplant (United Kingdom), Horizon2020 grant ERC-2014-CoG-64765, and a Cancer Research UK Programme Foundation Award to S.M.-F., who was also supported in part by an International Early Career Scientist grant from the Howard Hughes Medical Institute. A.G.-G. received fellowships from the Ramón Areces and LaCaixa Foundations. C.K. was supported by Marie Curie Career Integration grant H2020-MSCA-IF-2015-708411.