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Updated: May 23, 2025

Generation of Human Brain Organoids for Mitochondrial Disease Modeling
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Modeling hereditary diffuse leukoencephalopathy with axonal spheroids using microglia-sufficient brain organoids.

Wei Jie Wong1, Yi Wen Zhu1, Hai Ting Wang1

  • 1Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Elife
|May 21, 2025
PubMed
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Mutations in colony stimulating factor-1 receptor (CSF-1R) cause Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). Patient-derived microglia show inflammation and impaired neuronal regulation, contributing to neurodegeneration.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a fatal adult-onset neurodegenerative disease.
  • Mutations in the colony stimulating factor-1 receptor (CSF-1R) gene are the most common cause of HDLS.
  • The role of CSF-1R in human microglia and its impact on neuronal health in HDLS remains incompletely understood.

Purpose of the Study:

  • To investigate how CSF-1R mutations affect human microglia function.
  • To determine the downstream consequences of microglial dysfunction on neuronal cells in HDLS.
  • To identify key molecular mechanisms driving neurodegeneration in HDLS.

Main Methods:

  • Generation of induced pluripotent stem cells (iPSCs) from HDLS patients and isogenic controls.
Keywords:
CSF1RHDLShumanimmunologyinflammationmacrophagemicrogliaorganoid

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  • Co-culture system of patient-derived macrophages and forebrain organoids.
  • Analysis of macrophage metabolism, inflammatory phenotype, and gene expression (RNA sequencing).

    • Main Results:

    • Patient-derived macrophages (iMacs) exhibited a metabolic shift towards glycolysis and reduced CSF-1 sensitivity.
    • iMacs displayed an activated inflammatory phenotype with increased IL-1β production.
    • Bulk RNA sequencing revealed a reactive state in iMacs, leading to impaired regulation of neuronal populations in organoid cultures.

    Conclusions:

    • Microglial dysregulation, particularly elevated IL-1β production, is a key contributor to the neurodegenerative environment in HDLS.
    • CSF-1R mutations directly impact microglial function, leading to detrimental effects on neuronal cells.
    • This study identifies specific pathways involved in HDLS pathogenesis, offering potential therapeutic targets.