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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| Format: | Article |
| Language: | English |
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Elsevier
2025-06-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725005480 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Alexandra M. Lish |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-19ae6ba0cfd841d892ed78777924df49 |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-19ae6ba0cfd841d892ed78777924df492025-08-20T03:07:50ZengElsevierCell Reports2211-12472025-06-0144611577710.1016/j.celrep.2025.115777Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple culturesAlexandra M. Lish0Nancy Ashour1Richard V. Pearse, II2Paige C. Galle3Gwendolyn A. Orme4Sarah E. Heuer5Courtney R. Benoit6Kellianne D. Alexander7Elyssa F.L. Grogan8Gizem Terzioglu9Allegra Scarpa10Andrew M. Stern11Nicholas Seyfried12Vilas Menon13Tracy L. Young-Pearse14Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USADepartment of Biochemistry, Emory School of Medicine, Atlanta, GA, USACenter for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for the Study of Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USAAnn Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124725005480CP: NeuroscienceCP: Stem cell research |
| spellingShingle | 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 Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures Cell Reports CP: Neuroscience CP: Stem cell research |
| title | Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures |
| title_full | Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures |
| title_fullStr | Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures |
| title_full_unstemmed | Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures |
| title_short | Astrocyte induction of disease-associated microglia is suppressed by acute exposure to fAD neurons in human iPSC triple cultures |
| title_sort | astrocyte induction of disease associated microglia is suppressed by acute exposure to fad neurons in human ipsc triple cultures |
| topic | CP: Neuroscience CP: Stem cell research |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725005480 |
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