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Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures

ABSTRACT: Advancements in human induced pluripotent stem cell (hiPSC) technology have enabled co-culture models for disease modeling in physiologically relevant systems. However, co-culturing protocols face challenges in usability and consistency. Here, we introduce a robust, reproducible hiPSC-derived co-culture system integrating astrocytes, neurons, and microglia. This model leverages cryopreserved cells, enabling co-cultures within 20 days post-thaw. Comparing monocultures and tri-cultures, we show how cell-cell interactions shape transcriptional and functional states across all three cell types. Neurons in tri-culture exhibit increased spine density and activity, while astrocytes and microglia show altered responses to proinflammatory stimulation. Surprisingly, astrocyte co-culture induces upregulation of disease-associated microglia (DAM) genes, including TREM2, SPP1, APOE, and GPNMB. Additionally, while familial Alzheimer’s disease neurons induce a prototypical inflammatory response in microglia, the DAM signature is significantly downregulated. Collectively, this study establishes a versatile human tri-culture model as a valuable resource for dissecting neuron-glia interactions and their role in neurodegenerative disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295330 | GEO | 2025/06/02

REPOSITORIES: GEO

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