Fully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer's disease

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.

Automated summary

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.