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

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

Summary: 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-deriv...

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Main Authors: Alexandra M. Lish, Nancy Ashour, Richard V. Pearse, II, Paige C. Galle, Gwendolyn A. Orme, Sarah E. Heuer, Courtney R. Benoit, Kellianne D. Alexander, Elyssa F.L. Grogan, Gizem Terzioglu, Allegra Scarpa, Andrew M. Stern, Nicholas Seyfried, Vilas Menon, Tracy L. Young-Pearse
Format: Article
Language:English
Published: Elsevier 2025-06-01
Series:Cell Reports
Subjects:
CP: Neuroscience
CP: Stem cell research
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725005480
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Summary:Summary: 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 tricultures, we demonstrate how cell-cell interactions shape transcriptional and functional states across all three cell types. Neurons in triculture exhibit increased spine density and activity, while astrocytes and microglia show altered responses to proinflammatory stimulation. Surprisingly, the presence of astrocytes induces upregulation of disease-associated microglia (DAM) genes, including TREM2, SPP1, APOE, and GPNMB in microglia. Additionally, while familial Alzheimer’s disease neurons induce a prototypical inflammatory response in microglia, the DAM signature is significantly dampened. Collectively, this study establishes a versatile human triculture model as a valuable resource for dissecting neuron-glia interactions and their role in neurodegenerative disease.
ISSN:2211-1247

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