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CRISPRi screens in human iPSC-derived astrocytes elucidate regulators of distinct inflammatory reactive states.
Leng, Kun; Rose, Indigo V L; Kim, Hyosung; Xia, Wenlong; Romero-Fernandez, Wilber; Rooney, Brendan; Koontz, Mark; Li, Emmy; Ao, Yan; Wang, Shinong; Krawczyk, Mitchell; Tcw, Julia; Goate, Alison; Zhang, Ye; Ullian, Erik M; Sofroniew, Michael V; Fancy, Stephen P J; Schrag, Matthew S; Lippmann, Ethan S; Kampmann, Martin.
Afiliação
  • Leng K; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA. kun.leng@ucsf.edu.
  • Rose IVL; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA. kun.leng@ucsf.edu.
  • Kim H; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA, USA. kun.leng@ucsf.edu.
  • Xia W; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA.
  • Romero-Fernandez W; Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • Rooney B; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
  • Koontz M; Departments of Neurology and Pediatrics, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Li E; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Ao Y; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA.
  • Wang S; Department of Ophthalmology, School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • Krawczyk M; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA, USA.
  • Tcw J; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
  • Goate A; Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Zhang Y; Department of Neurobiology, University of California, Los Angeles, Los Angeles, CA, USA.
  • Ullian EM; Interdepartmental PhD Program in Neuroscience, University of California, Los Angeles, Los Angeles, CA, USA.
  • Sofroniew MV; Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
  • Fancy SPJ; Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
  • Schrag MS; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Lippmann ES; Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Kampmann M; Nash Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nat Neurosci ; 25(11): 1528-1542, 2022 11.
Article em En | MEDLINE | ID: mdl-36303069
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes Induzidas / Doença de Alzheimer Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes Induzidas / Doença de Alzheimer Limite: Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article