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

Abstract

Summary 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 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 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.

Adrenergic nerve degeneration in bone marrow drives aging of the hematopoietic stem cell niche

“…Unless otherwise specified, all antibodies were used at a 1:100 dilution. All antibodies were anti-mouse and their specificity was validated in previous studies performed in our laboratory 25 , 28 , 36 , 43 , 54 , 61 .…”

Neuro–Immune Cell Units: A New Paradigm in Physiology

“…As for the PaNS, despite some evidence for the presence of cholinergic nerve fibers at hematopoietic sites (Figure 1), little is known of its role in hematopoiesis (26). In a recent study, Pierce et al (27) showed that expression of muscarinic receptor type 1 (CHRM1) in the CNS controls HSC release from the bone marrow via release of glucocorticoids from the hypothalamicpituitary-adrenal axis and not from local parasympathetic nerves. Sensory peptidergic innervation is also found in the bone marrow.…”

Bone Marrow Micro‐Environment in Normal and Deranged Hematopoiesis: Opportunities for Regenerative Medicine and Therapies

“…Circadian cycles originating in the suprachiasmatic nucleus modulate HSC trafficking via adrenergic signaling to bone marrow CXCL12‐secreting stromal cells . The central nervous system also influences hematopoietic development and HSC mobilization through cholinergic stimulation of the hypothalamic‐pituitary‐adrenal axis . Finally, non‐myelinating Schwann cells of the peripheral nervous system locally secrete TGF‐β that maintains HSC quiescence …”