Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer’s disease Journal Article
| Authors: | Guttikonda, S. R.; Sikkema, L.; Tchieu, J.; Saurat, N.; Walsh, R. M.; Harschnitz, O.; Ciceri, G.; Sneeboer, M.; Mazutis, L.; Setty, M.; Zumbo, P.; Betel, D.; de Witte, L. D.; Pe’er, D.; Studer, L. |
| Article Title: | Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer’s disease |
| Abstract: | Aberrant inflammation in the CNS has been implicated as a major player in the pathogenesis of human neurodegenerative disease. We developed a new approach to derive microglia from human pluripotent stem cells (hPSCs) and built a defined hPSC-derived tri-culture system containing pure populations of hPSC-derived microglia, astrocytes, and neurons to dissect cellular cross-talk along the neuroinflammatory axis in vitro. We used the tri-culture system to model neuroinflammation in Alzheimer’s disease with hPSCs harboring the APPSWE+/+ mutation and their isogenic control. We found that complement C3, a protein that is increased under inflammatory conditions and implicated in synaptic loss, is potentiated in tri-culture and further enhanced in APPSWE+/+ tri-cultures due to microglia initiating reciprocal signaling with astrocytes to produce excess C3. Our study defines the major cellular players contributing to increased C3 in Alzheimer’s disease and presents a broadly applicable platform to study neuroinflammation in human disease. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Journal Title: | Nature Neuroscience |
| Volume: | 24 |
| Issue: | 3 |
| ISSN: | 1097-6256 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2021-03-01 |
| Start Page: | 343 |
| End Page: | 354 |
| Language: | English |
| DOI: | 10.1038/s41593-020-00796-z |
| PUBMED: | 33558694 |
| PROVIDER: | scopus |
| PMCID: | PMC8382543 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2021 -- Source: Scopus |
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