FGF-23 from erythroblasts promotes hematopoietic progenitor mobilization

Author:

Ishii Shinichi1,Suzuki Tomohide1,Wakahashi Kanako1,Asada Noboru1,Kawano Yuko1,Kawano Hiroki1,Sada Akiko1,Minagawa Kentaro1,Nakamura Yukio2,Mizuno Seiya3,Takahashi Satoru3456ORCID,Matsui Toshimitsu7,Katayama Yoshio1

Affiliation:

1. Division of Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan;

2. Cell Engineering Division, RIKEN BioResource Research Center, Ibaraki, Japan;

3. Transborder Medical Research Center (TMRC),

4. Department of Anatomy and Embryology, Faculty of Medicine,

5. International Institute for Integrative Sleep Medicine (WPI-IIIS), and

6. Life Science Center, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan; and

7. Department of Hematology, Nishiwaki Municipal Hospital, Nishiwaki, Japan

Abstract

Abstract Fibroblast growth factor 23 (FGF-23) hormone is produced by bone-embedded osteocytes and regulates phosphate homeostasis in kidneys. We found that administration of granulocyte colony-stimulating factor (G-CSF) to mice induced a rapid, substantial increase in FGF-23 messenger RNA in bone marrow (BM) cells. This increase originated mainly from CD45−Ter119+CD71+ erythroblasts. FGF-23 protein in BM extracellular fluid was markedly increased during G-CSF–induced hematopoietic progenitor cell (HPC) mobilization, but remained stable in the blood, with no change in the phosphate level. Consistent with the BM hypoxia induced by G-CSF, low oxygen concentration induced FGF-23 release from human erythroblast HUDEP-2 cells in vitro. The efficient mobilization induced by G-CSF decreased drastically in both FGF-23−/− and chimeric mice with FGF-23 deficiency, only in hematopoietic cells, but increased in osteocyte-specific FGF-23−/− mice. This finding suggests that erythroblast-derived, but not bone-derived, FGF-23 is needed to release HPCs from BM into the circulation. Mechanistically, FGF-23 did not influence CXCL-12 binding to CXCR-4 on progenitors but interfered with their transwell migration toward CXCL-12, which was canceled by FGF receptor inhibitors. These results suggest that BM erythroblasts facilitate G-CSF–induced HPC mobilization via FGF-23 production as an intrinsic suppressor of chemoattraction.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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