Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer's disease.
| Publication Type | Academic Article |
| Authors | Guttikonda S, Sikkema L, Tchieu J, Saurat N, Walsh R, Harschnitz O, Ciceri G, Sneeboer M, Mazutis L, Setty M, Zumbo P, Betel D, de Witte L, Pe'er D, Studer L |
| Journal | Nat Neurosci |
| Volume | 24 |
| Issue | 3 |
| Pagination | 343-354 |
| Date Published | 02/08/2021 |
| ISSN | 1546-1726 |
| Keywords | Alzheimer Disease, Complement C3, Microglia, Pluripotent Stem Cells |
| 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. |
| DOI | 10.1038/s41593-020-00796-z |
| PubMed ID | 33558694 |
| PubMed Central ID | PMC8382543 |