Cholinergic Signals from the CNS Regulate G-CSF-Mediated HSC Mobilization from Bone Marrow via a Glucocorticoid Signaling Relay

• DOI: 10.1016/j.stem.2017.01.002
• Publication Date: 2017-02-09T21:02:21Z
• Authors: Halley Pierce; Dachuan Zhang; Claire Magnon; Daniel Lucas; John R. Christin; Matthew Huggins; Gary J. Schwartz; Paul S. Frenette
• Keywords: Central Nervous System; 0303 health sciences; Reverse Transcriptase Polymerase Chain Reaction; Receptor, Muscarinic M1; Fluorescent Antibody Technique; Bone Marrow Cells; Flow Cytometry; Hematopoietic Stem Cell Mobilization; Mice, Mutant Strains; 3. Good health; Mice; 03 medical and health sciences; Cell Line, Tumor; Granulocyte Colony-Stimulating Factor; Animals; Humans; Glucocorticoids; In Situ Hybridization; Signal Transduction

Hematopoietic stem cells (HSCs) are mobilized from niches in the bone marrow (BM) to the blood circulation by the cytokine granulocyte colony-stimulating factor (G-CSF) through complex mechanisms. Among these, signals from the sympathetic nervous system regulate HSC egress via its niche, but how the brain communicates with the BM remains largely unknown. Here we show that muscarinic receptor type-1 (Chrm1) signaling in the hypothalamus promotes G-CSF-elicited HSC mobilization via hormonal priming of the hypothalamic-pituitary-adrenal (HPA) axis. Blockade of Chrm1 in the CNS, but not the periphery, reduces HSC mobilization. Mobilization is impaired in Chrm1-∕- mice and rescued by parabiosis with wild-type mice, suggesting a relay by a blood-borne factor. We have identified the glucocorticoid (GC) hormones as critical for optimal mobilization. Physiological levels of corticosterone promote HSC migration via the GC receptor Nr3c1-dependent signaling and upregulation of actin-organizing molecules. These results uncover long-range regulation of HSC migration emerging from the brain.