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Altered Inflammatory Signature in a C9ORF72 -ALS iPSC-Derived Motor Neuron and Microglia Coculture Model.
Yujing Gao1, Jessica L Brothwood1, Harpreet Saini1
1Astex Pharmaceuticals, Cambridge, UK.
Glia
|September 15, 2025
Summary
Researchers studied microglia
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) involves motor neuron degeneration and neuroinflammation.
- Microglia, a type of immune cell, play a key role in ALS neuroinflammation, but their exact mechanisms are unclear.
Purpose of the Study:
- To investigate the role of microglia in C9ORF72-associated ALS pathogenesis.
- To develop and utilize human induced pluripotent stem cell (iPSC)-derived models for studying ALS.
Main Methods:
- Generated iPSC-derived motor neuron and microglia cocultures using ALS patient cells with C9ORF72 hexanucleotide repeat expansion (HRE) and C9ORF72 knockout (KO) lines.
- Performed phenotypic assessments and single-cell RNA sequencing on cocultures.
- Stimulated microglia with lipopolysaccharide (LPS) to analyze inflammatory responses.
Main Results:
- Dysfunctional expression and secretion of inflammatory cytokines/chemokines were observed in C9ORF72 HRE and C9ORF72 KO microglia.
- Single-cell RNA sequencing revealed cell type-specific transcriptomic changes.
- An LPS-responsive microglia subpopulation was removed, correlating with a dampened inflammatory response in C9ORF72 HRE and C9ORF72 KO microglia.
Conclusions:
- Microglia play a critical role in ALS neuroinflammation.
- iPSC-derived coculture models are valuable for mechanistic studies of ALS-associated pathways.
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