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Early Fate Defines Microglia and Non-parenchymal Brain Macrophage Development

Sebastian G Utz1, Peter See2, Wiebke Mildenberger1

  • 1Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.

Cell
|April 8, 2020
PubMed

Insights

Central nervous system (CNS) macrophages, including microglia and border-associated macrophages (BAMs), originate from distinct developmental pathways. This study reveals their separate ontogeny and unique TGF-β dependency for development.

Area of Science:

  • Neuroimmunology
  • Developmental Biology
  • Cellular and Molecular Neuroscience

Background:

  • Central nervous system (CNS) macrophages consist of microglia and border-associated macrophages (BAMs), found in the meninges, choroid plexus, and perivascular spaces.
  • While most CNS macrophages develop during embryogenesis, choroid plexus and dural macrophages are adult monocyte-derived, raising questions about microglia and BAM developmental origins.
  • The shared or distinct developmental programs of microglia and BAMs remain largely unknown.

Purpose of the Study:

  • To investigate the ontogeny and developmental requirements of distinct CNS macrophage populations, specifically microglia and BAMs.
  • To determine if microglia and BAMs arise from separate lineages and identify their progenitor sources.
  • To elucidate the role of TGF-β in the development of these macrophage populations.

Main Methods:

  • Identification of distinct brain macrophage populations based on phenotypic, transcriptional, and spatial characteristics during development.
  • Utilizing fate-mapping models to trace the developmental origins of microglia and BAMs.
  • Investigating the dependency of microglia and BAM development on TGF-β signaling.

Main Results:

  • Two distinct brain macrophage populations, precursors to microglia and BAMs, were identified early in development, with evidence of segregation already present in the yolk sac.
  • Fate-mapping revealed that BAMs primarily originate from early erythro-myeloid progenitors in the yolk sac.
  • Microglia development was found to be dependent on TGF-β, whereas BAM genesis proceeded independently of this cytokine.

Conclusions:

  • Developing parenchymal (microglia) and non-parenchymal (BAMs) brain macrophages represent separate entities with distinct ontogenetic origins.
  • These macrophage populations exhibit unique gene signatures and differential requirements for TGF-β during their development.
  • The findings clarify the separate developmental trajectories of key CNS macrophage populations.

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