Flt3+ macrophage precursors commit sequentially to osteoclasts, dendritic cells and microglia

BMC Immunol. 2002 Oct 24:3:15. doi: 10.1186/1471-2172-3-15.

Abstract

Background: Macrophages, osteoclasts, dendritic cells, and microglia are highly specialized cells that belong to the mononuclear phagocyte system. Functional and phenotypic heterogeneity within the mononuclear phagocyte system may reveal differentiation plasticity of a common progenitor, but developmental pathways leading to such diversity are still unclear.

Results: Mouse bone marrow cells were expanded in vitro in the presence of Flt3-ligand (FL), yielding high numbers of non-adherent cells exhibiting immature monocyte characteristics. Cells expanded for 6 days, 8 days, or 11 days (day 6-FL, day 8-FL, and day 11-FL cells, respectively) exhibited constitutive potential towards macrophage differentiation. In contrast, they showed time-dependent potential towards osteoclast, dendritic, and microglia differentiation that was detected in day 6-, day 8-, and day 11-FL cells, in response to M-CSF and receptor activator of NFkappaB ligand (RANKL), granulocyte-macrophage colony stimulating-factor (GM-CSF) and tumor necrosis factor-alpha (TNFalpha), and glial cell-conditioned medium (GCCM), respectively. Analysis of cell proliferation using the vital dye CFSE revealed homogenous growth in FL-stimulated cultures of bone marrow cells, demonstrating that changes in differential potential did not result from sequential outgrowth of specific precursors.

Conclusions: We propose that macrophages, osteoclasts, dendritic cells, and microglia may arise from expansion of common progenitors undergoing sequential differentiation commitment. This study also emphasizes differentiation plasticity within the mononuclear phagocyte system. Furthermore, selective massive cell production, as shown here, would greatly facilitate investigation of the clinical potential of dendritic cells and microglia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / physiology
  • Carrier Proteins / pharmacology
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cells, Cultured
  • Culture Media, Conditioned / pharmacology
  • Dendritic Cells / cytology
  • Dendritic Cells / physiology*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Macrophage Colony-Stimulating Factor / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / physiology*
  • Membrane Glycoproteins / pharmacology
  • Membrane Proteins / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Microglia / cytology
  • Microglia / physiology*
  • Osteoclasts / cytology
  • Osteoclasts / physiology*
  • Proto-Oncogene Proteins / biosynthesis*
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptor Protein-Tyrosine Kinases / biosynthesis*
  • Stem Cells / cytology
  • Stem Cells / drug effects
  • Stem Cells / physiology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • fms-Like Tyrosine Kinase 3

Substances

  • Carrier Proteins
  • Culture Media, Conditioned
  • Membrane Glycoproteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • Tumor Necrosis Factor-alpha
  • flt3 ligand protein
  • Macrophage Colony-Stimulating Factor
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Flt3 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3