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Series GSE139550 Query DataSets for GSE139550
Status Public on Nov 22, 2020
Title Fully defined human PSC-derived microglia and tri-culture system reveals cell type specific potentiation of complement C3 production in a model of Alzheimer’s disease [scRNA-seq]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Aberrant inflammation in the central nervous system (CNS) has been implicated as a major player in the pathogenesis of human neurodegenerative disease. However, the specific contribution of each cell type to the neuroinflammatory axis in vivo remains unclear with species-specific differences in key signaling pathways further complicating the challenge. To assemble a fully human platform to study neuroinflammation, we first developed a novel approach to derive microglia from human pluripotent stem cells (hPSCs) that faithfully recapitulates microglial ontogeny as validated by single cell RNA-sequencing and stage-specific mapping onto datasets of developing mouse microglia. Using these cells, we build the first defined and completely hPSC-derived tri-culture system containing pure populations of hPSC-derived microglia, astrocytes, and neurons to dissect cellular crosstalk along the neuroinflammatory axis in vitro. We next used the tri-culture system to model neuroinflammation in Alzheimer’s Disease using hPSCs harboring the APPSWE+/+ mutation and their isogenic control. Our data reveal that production of complement C3, a protein that is increased under inflammatory conditions and implicated in synaptic loss, is potentiated under tri-culture conditions, and is further enhanced in APPSWE+/+ tri-cultures. Using cell type-specific ablation studies, we report that C3 potentiation is due to the presence of a neuroinflammatory loop in which microglia are the key initiators that activate reciprocal signaling with astrocytes to produce excess C3. Our study defines the major cellular players contributing to increased C3 in AD and presents a broadly applicable platform to study neuroinflammation in human disease.
Overall design Cell heterogeneity was assessed at timepoints during in vitro human primitive hematopoiesis using single-cell RNA-sequencing to identify the early trajectories of differentiating microglial cells.
Contributor(s) Guttikonda SR, Sikkema L, Tchieu J, Saurat N, Walsh R, Ciceri G, Sneeboer M, Mazutis L, Setty M, de Witte LD, Pe'er D, Studer L
Citation(s) 33558694
Submission date Oct 29, 2019
Last update date Mar 18, 2021
Contact name Sudha Guttikonda
Organization name MSKCC
Department Developmental Biology
Lab Studer Lab
Street address 430 E 67th St
City New York
State/province New York
ZIP/Postal code 10065
Country USA
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (4)
GSM4143592 Day4
GSM4143593 Day8_accutase
GSM4143594 Day8_suspension
This SubSeries is part of SuperSeries:
GSE139552 Fully defined human PSC-derived microglia and tri-culture system reveals cell type specific potentiation of complement C3 production in a model of Alzheimer’s disease
BioProject PRJNA580245
SRA SRP227359

Download family Format
SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE139550_RAW.tar 116.1 Mb (http)(custom) TAR (of CSV)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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