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Updated: Aug 6, 2025
Derivation of a Human Brain Organoid with Microglia Development
Published on: January 17, 2025
Microglia-containing cerebral organoids derived from induced pluripotent stem cells for the study of neurological
Yiling Hong1, Xu Dong2, Lawrence Chang2
1College of Veterinary Medicine, Western University of Health Sciences, Pomona, CA 91766-1854, USA.
Abstract:
Microglia play an important role in neuroinflammation and neurodegeneration. Here, we report an approach for generating microglia-containing cerebral organoids derived from human pluripotent stem cells involving the supplementation of growth factors (FGF, EGF, heparin) and 10% CO2 culture conditions. Using this platform, Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC) cerebral organoids were generated from patient-derived induced pluripotent stem cells (iPSCs). These ALS-PDC-affected organoids had more reactive astrocytes and M1 microglia, and had fewer M2 microglia than their unaffected counterparts, leading to impaired microglia-mediated phagocytosis. RNA-seq analysis of ALS-PDC and control organoids indicated that the most significant changes were microglia- and astrocyte-related genes (IFITM1/2, TGF-β, and GFAP). The most significantly downregulated pathway was type I interferon signaling. Interferon-gamma supplementation increased IFITM expression, enhanced microglia-mediated phagocytosis, and reduced beta-amyloid accumulation in ALS-PDC-affected network. The results demonstrated the feasibility of using microglia-containing organoids for the study of neurodegenerative diseases.
Insights
Researchers developed microglia-containing brain organoids from human stem cells to study neurodegenerative diseases like ALS-PDC. These organoids revealed altered microglia and astrocyte function, offering new insights into disease mechanisms.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Neurodegenerative Disease Research
Background:
- Microglia are crucial in neuroinflammation and neurodegeneration.
- Cerebral organoids offer a model for studying human brain development and disease.
- Patient-derived induced pluripotent stem cells (iPSCs) enable disease modeling.
Purpose of the Study:
- To develop a method for generating microglia-containing cerebral organoids from human pluripotent stem cells.
- To investigate the role of microglia and astrocytes in Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS-PDC) using these organoids.
- To identify potential therapeutic targets for ALS-PDC.
Main Methods:
- Supplementation of human pluripotent stem cells with growth factors (FGF, EGF, heparin) and 10% CO2 to generate microglia-containing cerebral organoids.
- Generation of ALS-PDC cerebral organoids from patient-derived iPSCs.
- RNA-sequencing (RNA-seq) analysis to compare gene expression profiles between ALS-PDC and control organoids.
- Interferon-gamma supplementation to assess its effect on microglia function and pathology.
Main Results:
- ALS-PDC organoids exhibited increased reactive astrocytes and M1 microglia, with decreased M2 microglia, leading to impaired microglia-mediated phagocytosis.
- RNA-seq identified significant changes in microglia- and astrocyte-related genes (IFITM1/2, TGF-β, GFAP) and downregulation of type I interferon signaling in ALS-PDC organoids.
- Interferon-gamma treatment enhanced IFITM expression, improved microglia phagocytosis, and reduced beta-amyloid accumulation in ALS-PDC organoids.
Conclusions:
- Microglia-containing cerebral organoids are a feasible platform for studying neurodegenerative diseases.
- The study highlights the dysregulation of microglia and astrocyte pathways, particularly type I interferon signaling, in ALS-PDC.
- Interferon-gamma shows therapeutic potential for improving microglia function and mitigating pathology in ALS-PDC.
