Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow.
Hematopoietic stem and progenitor cells (HSPC), attracted by the chemokine CXCL12, reside in specific niches in the bone marrow (BM). HSPC migration out of the BM is a critical process that underlies modern clinical stem cell transplantation. Here we demonstrate that enforced HSPC egress from BM niches depends critically on the nervous system. UDP-galactose ceramide galactosyltransferase-deficient (Cgt(-/-)) mice exhibit aberrant nerve conduction and display virtually no HSPC egress from BM following granulocyte colony-stimulating factor (G-CSF) or fucoidan administration. Adrenergic tone, osteoblast function, and bone CXCL12 are dysregulated in Cgt(-/-) mice. Pharmacological or genetic ablation of adrenergic neurotransmission indicates that norepinephrine (NE) signaling controls G-CSF-induced osteoblast suppression, bone CXCL12 downregulation, and HSPC mobilization. Further, administration of a beta(2) adrenergic agonist enhances mobilization in both control and NE-deficient mice. Thus, these results indicate that the sympathetic nervous system regulates the attraction of stem cells to their niche.
Katayama
Yoshio
Y
Department of Medicine, Immunobiology Center and Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
Battista
Michela
M
Kao
Wei-Ming
WM
Hidalgo
Andrés
A
Peired
Anna J
AJ
Thomas
Steven A
SA
Frenette
Paul S
PS
D000818:Animals; D000831:Animals, Newborn; D001854:Bone Marrow Cells / Q000187:drug effects*; D002465:Cell Movement; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D015536:Down-Regulation; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D011828:Radiation Chimera; D013564:Sympathetic Nervous System / Q000502:physiology*
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016179:Granulocyte Colony-Stimulating Factor