Role for vitamin D receptor in the neuronal control of the hematopoietic stem cell niche

• Published in: Blood 2010-12, Vol.116 (25), p.5528-5535
• Main Authors: Kawamori, Yuriko, Katayama, Yoshio, Asada, Noboru, Minagawa, Kentaro, Sato, Mari, Okamura, Atsuo, Shimoyama, Manabu, Nakagawa, Kimie, Okano, Toshio, Tanimoto, Mitsune, Kato, Shigeaki, Matsui, Toshimitsu
• Format: Article
• Language: English
• Subjects: Adrenergic Agonists - pharmacology; Animals; Biological and medical sciences; Blotting, Western; Calcium - administration & dosage; Cell Movement; Chemokine CXCL12 - metabolism; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Fluorescent Antibody Technique; Granulocyte Colony-Stimulating Factor - administration & dosage; Hematologic and hematopoietic diseases; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells - physiology; Leukocyte Common Antigens - physiology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoblasts - cytology; Osteoblasts - metabolism; RANK Ligand - genetics; RANK Ligand - metabolism; Receptors, Adrenergic, beta-1 - chemistry; Receptors, Calcitriol - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; Stem Cell Niche - physiology; Sympathetic Nervous System - metabolism; Vitamin D - analogs & derivatives; Vitamin D - pharmacology
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-04-279216

Hematopoietic stem/progenitor cells (HSPCs) are released from the bone marrow to the circulation by the cytokine, granulocyte colony-stimulating factor, via sympathetic nervous system (SNS)–mediated osteoblast suppression. Because the orientation of HSPCs in their osteoblastic niche is reported to be guided by [Ca2+], we speculated on a cooperation between the calcium-regulating hormones and SNS in the regulation of HSPC trafficking. Here, we present the severe impairment of granulocyte colony-stimulating factor–induced osteoblast suppression and subsequent HSPC mobilization in vitamin D receptor (VDR)–deficient mice. In osteoblasts, functional VDR possessing, at least in part, a transcriptional activity, was specifically induced by β2-adrenergic receptor (AR) agonists. While β2-AR agonists transiently increased mRNA expression of Vdr and its downstream gene, Rankl, 1α,25-dihydroxyvitamin-D3 sustained the β2-AR–induced Rankl expression at high level by stabilizing VDR protein. These data suggest that VDR is essential for durable β2-AR signaling in the stem cell niche. Our study demonstrates not only a novel function of VDR as a critical modulator of HSPC trafficking, but also the presence of a SNS-mediated, bone-remodeling mechanism through VDR. VDR contributes to brain-bone-blood integration in an unanticipated way distinct from other classical calcium-regulating hormones.