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

Halley Pierce, Dachuan Zhang, Claire Magnon, Daniel Lucas, John R. Christin, Matthew Huggins, Gary J. Schwartz, Paul S. Frenette

Research output: Contribution to journalArticle

23 Citations (Scopus)

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. Pierce et al. show that the muscarinic receptor type-1 (Chrm1) expression in the brain regulates HSC mobilization from bone marrow via the hypothalamic-pituitary-adrenal axis, leading to glucocorticoid-mediated control of actin organization pathways.

Original languageEnglish (US)
JournalCell Stem Cell
DOIs
StateAccepted/In press - Sep 28 2016

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Hematopoietic Stem Cell Mobilization
Granulocyte Colony-Stimulating Factor
Hematopoietic Stem Cells
Cholinergic Agents
Glucocorticoids
Bone Marrow
Muscarinic Receptors
Cell Movement
Actins
Brain
Parabiosis
Stem Cell Niche
Blood Circulation
Sympathetic Nervous System
Glucocorticoid Receptors
Corticosterone
Hypothalamus
Up-Regulation
Hormones
Cytokines

Keywords

  • Hematopoietic stem cell mobilization
  • Hyphothalamic-pituitary-adrenal axis
  • Muscarinic receptor type-1

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

Cite this

Cholinergic Signals from the CNS Regulate G-CSF-Mediated HSC Mobilization from Bone Marrow via a Glucocorticoid Signaling Relay. / Pierce, Halley; Zhang, Dachuan; Magnon, Claire; Lucas, Daniel; Christin, John R.; Huggins, Matthew; Schwartz, Gary J.; Frenette, Paul S.

In: Cell Stem Cell, 28.09.2016.

Research output: Contribution to journalArticle

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