title: Cholinergic Signals from the CNS Regulate G-CSF-Mediated HSC Mobilization from Bone Marrow via a Glucocorticoid Signaling Relay.
abstract: 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.
authors.affiliation: The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Halley
authors.initials: H
authors.lastname: Pierce
authors.affiliation: The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Dachuan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Claire
authors.initials: C
authors.lastname: Magnon
authors.affiliation: The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lucas
authors.affiliation: The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Christin
authors.affiliation: The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Huggins
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, New York, NY 10461, USA; Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schwartz
authors.affiliation: The Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, New York, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, New York, NY 10461, USA. Electronic address: paul.frenette@einstein.yu.edu.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005938:Glucocorticoids / Q000494:pharmacology*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D017403:In Situ Hybridization; D051379:Mice; D008817:Mice, Mutant Strains; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C086088:CHRM1 protein, human; D005938:Glucocorticoids; D043643:Receptor, Muscarinic M1; D016179:Granulocyte Colony-Stimulating Factor
keywords: hematopoietic stem cell mobilization; hyphothalamic-pituitary-adrenal axis; muscarinic receptor type-1