期刊
NATURE NEUROSCIENCE
卷 24, 期 3, 页码 343-354出版社
NATURE PORTFOLIO
DOI: 10.1038/s41593-020-00796-z
关键词
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资金
- Ruth L. Kirschstein Individual Predoctoral NRSA [1F30MH115616-01]
- Medical Scientist Training Program grant from the NIH National Institute of General Medical Sciences [T32GM007739]
- Tri-I Starr Stem Cell Scholar fellowship
- Glenn/AFAR Postdoctoral Fellowship
- F32 Ruth L. Kirschstein Postdoctoral fellowship [MH116590]
- EMBO long-term postdoctoral fellowship
- NYSTEM postdoctoral fellowship
- [R21 NS084334]
- [1R01AG056298]
- [P30CA008748]
The study utilizes a human pluripotent stem cell-derived tri-culture system to model neuroinflammation in Alzheimer's disease and identifies the critical role of reciprocal signaling between microglia and astrocytes in exacerbating the inflammatory response.
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 APP(SWE)+/+ 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 APP(SWE)+/+ 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. Guttikonda et al. engineered a human pluripotent stem cell-derived tri-culture system containing microglia, astrocytes, and neurons. This system recapitulates cell-type-specific inflammatory signaling in an in vitro model of Alzheimer's disease.
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