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

Overview

abstract

  • 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 APPSWE+/+ 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 APPSWE+/+ 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.

publication date

  • February 8, 2021

Research

keywords

  • Alzheimer Disease
  • Complement C3
  • Microglia
  • Pluripotent Stem Cells

Identity

PubMed Central ID

  • PMC8382543

Scopus Document Identifier

  • 85100712391

Digital Object Identifier (DOI)

  • 10.1038/nprot.2013.143

PubMed ID

  • 33558694

Additional Document Info

volume

  • 24

issue

  • 3