CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states

Kun Leng, Indigo V.L. Rose, Hyosung Kim, Wenlong Xia, Wilber Romero-Fernandez, Brendan Rooney, Mark Koontz, Emmy Li, Yan Ao, Shinong Wang, Mitchell Krawczyk, Julia Tcw, Alison Goate, Ye Zhang, Erik M. Ullian, Michael V. Sofroniew, Stephen P.J. Fancy, Matthew S. Schrag, Ethan S. Lippmann, Martin Kampmann

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Astrocytes become reactive in response to insults to the central nervous system by adopting context-specific cellular signatures and outputs, but a systematic understanding of the underlying molecular mechanisms is lacking. In this study, we developed CRISPR interference screening in human induced pluripotent stem cell-derived astrocytes coupled to single-cell transcriptomics to systematically interrogate cytokine-induced inflammatory astrocyte reactivity. We found that autocrine–paracrine IL-6 and interferon signaling downstream of canonical NF-κB activation drove two distinct inflammatory reactive signatures, one promoted by STAT3 and the other inhibited by STAT3. These signatures overlapped with those observed in other experimental contexts, including mouse models, and their markers were upregulated in human brains in Alzheimer’s disease and hypoxic-ischemic encephalopathy. Furthermore, we validated that markers of these signatures were regulated by STAT3 in vivo using a mouse model of neuroinflammation. These results and the platform that we established have the potential to guide the development of therapeutics to selectively modulate different aspects of inflammatory astrocyte reactivity.

Original languageEnglish
Pages (from-to)1528-1542
Number of pages15
JournalNature Neuroscience
Volume25
Issue number11
DOIs
StatePublished - Nov 2022

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