Assessing Gq-GPCR–induced human astrocyte reactivity using bioengineered neural organoids

Caroline Cvetkovic, Rajan Patel, Arya Shetty, Matthew K. Hogan, Morgan Anderson, Nupur Basu, Samira Aghlara-Fotovat, Srivathsan Ramesh, Debosmita Sardar, Omid Veiseh, Michael E. Ward, Benjamin Deneen, Philip J. Horner, Robert Krencik

Research output: Contribution to journalArticlepeer-review

Abstract

Astrocyte reactivity can directly modulate nervous system function and immune responses during disease and injury. However, the consequence of human astrocyte reactivity in response to specific contexts and within neural networks is obscure. Here, we devised a straightforward bioengineered neural organoid culture approach entailing transcription factor–driven direct differentiation of neurons and astrocytes from human pluripotent stem cells combined with genetically encoded tools for dual cell-selective activation. This strategy revealed that Gq-GPCR activation via chemogenetics in astrocytes promotes a rise in intracellular calcium followed by induction of immediate early genes and thrombospondin 1. However, astrocytes also undergo NF-κB nuclear translocation and secretion of inflammatory proteins, correlating with a decreased evoked firing rate of cocultured optogenetic neurons in suboptimal conditions, without overt neurotoxicity. Altogether, this study clarifies the intrinsic reactivity of human astrocytes in response to targeting GPCRs and delivers a bioengineered approach for organoid-based disease modeling and preclinical drug testing.

Original languageEnglish (US)
Article numbere202107135
JournalJournal of Cell Biology
Volume221
Issue number4
DOIs
StatePublished - Apr 4 2022

Keywords

  • Cell signaling
  • Neuroscience
  • Stem cells

ASJC Scopus subject areas

  • Cell Biology

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