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

Autor: Guttikonda SR; The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA., Sikkema L; Computational and Systems Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Metastasis & Tumor Ecosystems Center, Sloan Kettering Institute for Cancer Research, New York, NY, USA., Tchieu J; The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA., Saurat N; The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA., Walsh RM; The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA., Harschnitz O; The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA., Ciceri G; The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA., Sneeboer M; Institute for Computational Biomedicine, Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA., Mazutis L; Computational and Systems Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Metastasis & Tumor Ecosystems Center, Sloan Kettering Institute for Cancer Research, New York, NY, USA., Setty M; Computational and Systems Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Metastasis & Tumor Ecosystems Center, Sloan Kettering Institute for Cancer Research, New York, NY, USA., Zumbo P; Applied Bioinformatics Core & Department of Physiology and Biophysics, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY, USA., Betel D; Institute for Computational Biomedicine, Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA., de Witte LD; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY Mount Sinai Medical Center, New York, NY, USA.; Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands., Pe'er D; Computational and Systems Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA.; Metastasis & Tumor Ecosystems Center, Sloan Kettering Institute for Cancer Research, New York, NY, USA., Studer L; The Center for Stem Cell Biology, Sloan Kettering Institute for Cancer Research, New York, NY, USA. studerl@mskcc.org.; Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA. studerl@mskcc.org.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2021 Mar; Vol. 24 (3), pp. 343-354. Date of Electronic Publication: 2021 Feb 08.
DOI: 10.1038/s41593-020-00796-z
Abstrakt: 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.
Databáze: MEDLINE
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