Neuroinflammatory astrocytes generated from cord blood-derived human induced pluripotent stem cells

Qiong Zhou, Coralie Viollet, Anastasia Efthymiou, Guzal Khayrullina, Kasey E. Moritz, Matthew D. Wilkerson, Gauthaman Sukumar, Clifton L. Dalgard, Martin L. Doughty*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Background: Astrocytes respond to central nervous system (CNS) injury and disease by transforming to a reactive astrogliosis cell state that can contribute to either CNS dysfunction or repair. Neuroinflammation is a powerful driver of a harmful A1 astrogliosis phenotype associated with in vitro neurotoxicity and histopathology in human neurodegenerative diseases. Here we report a protocol for the rapid development of a human cell culture model of neuroinflammatory astrogliosis using induced pluripotent stem cells (iPSCs). Methods: Using RNA sequencing and in vitro cell assays, we measured transcriptional and cellular effects of chronic exposure of human iPSC-derived astrocytes to the cytokines TNFα (tumor necrosis factor alpha) or IL-1β (interleukin-1 beta). Results: We show TNFα and IL-1β induce pro-inflammatory gene signatures but by widely different magnitudes. TNFα treatment results in 606 differential expressed genes, the suppression of glutamate-uptake, and increased phagocytic activity in astrocyte cultures. In contrast, IL-1β effects are attenuated to 33 differential expressed genes and no significant effects on glutamate-uptake or increased phagocytic activity. Conclusion: Our approach demonstrates a rapid tool for modeling neuroinflammatory human astrocytic responses in nervous system trauma and disease. In particular, we reveal a model for robust TNFα-induced human astrogliosis suitable for the study of neurotoxic A1 astrocytes.

Original languageEnglish
Article number164
JournalJournal of Neuroinflammation
Volume16
Issue number1
DOIs
StatePublished - 9 Aug 2019
Externally publishedYes

Keywords

  • Astrocyte
  • Glutamate uptake
  • Human induced pluripotent stem cell
  • Phagocytosis
  • RNA sequencing

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