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Suppression of CXCL12 production by bone marrow osteoblasts is a common and critical pathway for cytokine-induced

Matthew J Christopher1, Fulu Liu, Matthew J Hilton

  • 1Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.

Blood
|January 15, 2009
PubMed

Insights

Granulocyte colony-stimulating factor (G-CSF) mobilizes hematopoietic stem/progenitor cells (HSPCs) by disrupting CXCR4 signaling and VLA-4 function independently. Osteoblast-mediated CXCL12 loss is a key step in cytokine-induced HSPC mobilization.

Area of Science:

  • Hematology
  • Stem Cell Biology
  • Immunology

Background:

  • Granulocyte colony-stimulating factor (G-CSF) mobilizes hematopoietic stem/progenitor cells (HSPCs) through complex mechanisms involving bone marrow proteases, adhesion molecules, and CXCL12/CXCR4 signaling.
  • The independent contributions and overlaps of these mobilization pathways remain unclear.
  • Understanding these mechanisms is crucial for optimizing HSPC transplantation and regenerative medicine.

Purpose of the Study:

  • To elucidate the distinct roles of CXCR4 signaling and VLA-4 function in G-CSF-mediated HSPC mobilization.
  • To investigate whether other cytokines, such as Flt3 ligand (Flt3L) and stem cell factor (SCF), also disrupt CXCR4 signaling.
  • To identify the cellular and molecular basis for cytokine-induced changes in CXCL12 expression.

Main Methods:

  • Utilized CXCR4(-/-) bone marrow chimeras to assess HSPC mobilization by G-CSF, Grobeta, and a VLA-4 antagonist.
  • Characterized CXCR4 and CXCL12 expression in the bone marrow following HSPC mobilization with Flt3L and SCF.
  • Employed RNA in situ hybridization and cell sorting to determine the source of CXCL12 downregulation.

Main Results:

  • HSPC mobilization by G-CSF and Grobeta was dependent on CXCR4, while VLA-4 antagonist-mediated mobilization was intact.
  • Flt3L and SCF treatments significantly reduced bone marrow CXCL12 expression and surface CXCR4 on HSPCs.
  • Decreased CXCL12 expression was attributed to a loss of osteoblast lineage cells, suggesting a common pathway in cytokine-induced mobilization.

Conclusions:

  • Disruption of CXCR4 signaling and VLA-4 pathway attenuation represent independent mechanisms for G-CSF-induced HSPC mobilization.
  • Reduced CXCL12 expression by osteoblasts is a critical and common event in cytokine-driven HSPC mobilization.
  • These findings provide a deeper understanding of HSPC trafficking and potential therapeutic targets.

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