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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
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iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer

Dong Shin Park1,2, Tatsuya Kozaki1, Satish Kumar Tiwari1

  • 1Singapore Immunology Network (SIgN), Agency for Science, Technology and Research, Singapore, Singapore.

Nature
|November 2, 2023
PubMed

Insights

Researchers developed microglia-sufficient brain organoids by adding primitive macrophages. These engineered microglia (iMicro) regulate neuronal development and promote axon growth through lipid transport, advancing brain organoid models.

Area of Science:

  • Neuroscience
  • Developmental Biology
  • Stem Cell Biology

Background:

  • Microglia, brain-resident macrophages, are crucial for brain development but their early human roles are unclear.
  • Existing human brain organoids lack microglia, limiting their ability to model early brain development and maturation.
  • Limited access to human embryonic brain tissue hinders the study of microglial function in early neurodevelopment.

Purpose of the Study:

  • To generate microglia-sufficient human brain organoids.
  • To investigate the role of microglia in human brain organoid maturation and neuronal development.
  • To elucidate the mechanisms of microglial-neuronal crosstalk in the developing brain.

Main Methods:

  • Coculturing human induced pluripotent stem cell-derived brain organoids with primitive macrophages (iMac).
  • Generating microglia-like cells (iMicro) from iMac within the organoid system.
  • Analyzing the impact of iMicro on neuronal progenitor cell (NPC) proliferation and differentiation, including axonogenesis.

Main Results:

  • iMac differentiated into microglia-like cells (iMicro) that modulated NPC differentiation.
  • iMicro limited NPC proliferation and promoted axonogenesis in brain organoids.
  • A novel pathway of lipid-mediated crosstalk involving PLIN2+ lipid droplets and cholesterol export from iMicro to NPCs was identified, enhancing neurogenesis.

Conclusions:

  • The development of microglia-sufficient brain organoids provides a powerful new model for studying human neurodevelopment.
  • Microglia play a significant role in regulating early neurogenesis and axon development through lipid metabolism.
  • This study uncovers a critical microglial-NPC communication pathway essential for neurogenesis in the human brain.

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