Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer’s disease
- 8 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Neuroscience
- Vol. 24 (3), 343-354
- https://doi.org/10.1038/s41593-020-00796-z
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (1F30MH115616)
- Tri-I Starr Stem Cell Scholar fellowship
- Glenn/AFAR Postdoctoral Fellowship
- NYSTEM Fellowship
- EMBO fellowship
- U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (R21NS084334)
This publication has 64 references indexed in Scilit:
- Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathwaysNature Neuroscience, 2013
- IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microgliaNature Immunology, 2012
- Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent MannerNeuron, 2012
- Physiological function of microgliaNeuron Glia Biology, 2011
- Ensembl BioMarts: a hub for data retrieval across taxonomic spaceDatabase: The Journal of Biological Databases and Curation, 2011
- Fate Mapping Analysis Reveals That Adult Microglia Derive from Primitive MacrophagesScience, 2010
- Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signalingNature Biotechnology, 2009
- The Classical Complement Cascade Mediates CNS Synapse EliminationCell, 2007
- Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in VivoScience, 2005
- Localization and Cell Association of C1q in Alzheimer's Disease BrainExperimental Neurology, 1996