Open AccessFully defined human pluripotent stem cell-derived microglia and tri-culture system model C3 production in Alzheimer’s disease
Author(s) -
Sudha R Guttikonda,
Lisa Sikkema,
Jason Tchieu,
Nathalie Saurat,
Ryan Walsh,
Oliver Harschnitz,
Gabriele Ciceri,
Marjolein Sneeboer,
Linas Mažutis,
Manu Setty,
Paul Zumbo,
Doron Betel,
Lot de Witte,
Dana Pe’er,
Lorenz Studer
Publication year - 2021
Publication title -
nature neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 13.403
H-Index - 422
eISSN - 1546-1726
pISSN - 1097-6256
DOI - 10.1038/s41593-020-00796-z
Subject(s) - microglia , neuroinflammation , induced pluripotent stem cell , neuroscience , biology , microbiology and biotechnology , inflammation , immunology , embryonic stem cell , genetics , gene
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.