FGF-23 from erythroblasts promotes hematopoietic progenitor mobilization

Area of Science:

• Hematology
• Endocrinology
• Cell Biology

Background:

• Fibroblast growth factor 23 (FGF-23) is a hormone primarily produced by osteocytes, regulating phosphate homeostasis.
• Granulocyte colony-stimulating factor (G-CSF) is known to induce hematopoietic progenitor cell (HPC) mobilization from bone marrow (BM).
• The precise mechanisms by which G-CSF stimulates HPC release, particularly the role of local factors within the BM microenvironment, are not fully understood.

Purpose of the Study:

• To investigate the role of FGF-23 in G-CSF-induced HPC mobilization.
• To identify the cellular source of FGF-23 during G-CSF treatment.
• To elucidate the mechanism by which FGF-23 affects HPC mobilization.

Main Methods:

• Administration of G-CSF to mice and analysis of FGF-23 mRNA and protein levels in BM cells and blood.
• Identification of FGF-23 producing cells using cell surface markers (CD45, Ter119, CD71).
• In vitro experiments using human erythroblast cells (HUDEP-2) under low oxygen conditions.
• Studies using FGF-23 knockout mice (FGF-23-/-) and chimeric mice to assess the contribution of FGF-23 from different cell types.
• Assessment of HPC migration in response to CXCL-12 and the effect of FGF-23 and FGF receptor inhibitors.

Main Results:

• G-CSF administration rapidly increased FGF-23 mRNA in BM cells, primarily from erythroblasts.
• FGF-23 protein levels increased in BM extracellular fluid during G-CSF-induced HPC mobilization, but not in blood.
• Low oxygen conditions induced FGF-23 release from erythroblasts in vitro.
• G-CSF-induced HPC mobilization was significantly impaired in FGF-23 deficient mice (hematopoietic cell-specific deficiency) but not in osteocyte-specific FGF-23 deficient mice.
• FGF-23 interfered with the transwell migration of HPCs toward CXCL-12, an effect blocked by FGF receptor inhibitors.

Conclusions:

• Erythroblast-derived FGF-23, not bone-derived FGF-23, is crucial for G-CSF-induced HPC mobilization from the BM.
• FGF-23 acts as an intrinsic suppressor of HPC chemoattraction by interfering with migration towards CXCL-12.
• These findings reveal a novel mechanism where erythroblasts regulate HPC release via FGF-23 production, impacting hematopoietic stem cell mobilization.