title: Extracellular vesicles from neural stem cells transfer IFN-γ via Ifngr1 to activate Stat1 signaling in target cells.
abstract: The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. We described induction of interferon gamma (IFN-γ) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-γ bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we demonstrated that endogenous Stat1 and Ifngr1 in target cells are indispensable to sustain the activation of Stat1 signaling by EV-associated IFN-γ/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-γ/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system.
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, and NIHR Biomedical Research Centre, University of Cambridge, CB2 0PY Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cossetti
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, and NIHR Biomedical Research Centre, University of Cambridge, CB2 0PY Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge, UK.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Iraci
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, St Lucia QLD 4072, Australia.
authors.forename: Tim R
authors.initials: TR
authors.lastname: Mercer
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, and NIHR Biomedical Research Centre, University of Cambridge, CB2 0PY Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge, UK; The EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Leonardi
authors.affiliation: Biomolecular Mass Spectrometry Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Alpi
authors.affiliation: Biomolecular Mass Spectrometry Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy.
authors.forename: Denise
authors.initials: D
authors.lastname: Drago
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, and NIHR Biomedical Research Centre, University of Cambridge, CB2 0PY Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge, UK.
authors.forename: Clara
authors.initials: C
authors.lastname: Alfaro-Cervello
authors.affiliation: The EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Harpreet K
authors.initials: HK
authors.lastname: Saini
authors.affiliation: The EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Davis
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, and NIHR Biomedical Research Centre, University of Cambridge, CB2 0PY Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Schaeffer
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, and NIHR Biomedical Research Centre, University of Cambridge, CB2 0PY Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge, UK.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Vega
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, and NIHR Biomedical Research Centre, University of Cambridge, CB2 0PY Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge, UK.
authors.forename: Matilde
authors.initials: M
authors.lastname: Stefanini
authors.affiliation: Southwest Hospital, Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China.
authors.forename: CongJian
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK.
authors.forename: Werner
authors.initials: W
authors.lastname: Muller
authors.affiliation: Departamento de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, 46980 Valencia, Spain.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garcia-Verdugo
authors.affiliation: Department of Biochemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, Victoria 3086, Australia.
authors.forename: Suresh
authors.initials: S
authors.lastname: Mathivanan
authors.affiliation: Biomolecular Mass Spectrometry Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milano, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.affiliation: The EMBL-European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Enright
authors.affiliation: The Garvan Institute, Darlinghurst, NSW 2010, Australia.
authors.forename: John S
authors.initials: JS
authors.lastname: Mattick
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, and NIHR Biomedical Research Centre, University of Cambridge, CB2 0PY Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge, UK. Electronic address: spp24@cam.ac.uk.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pluchino
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001692:Biological Transport; D002450:Cell Communication; D060833:Cellular Microenvironment; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000637:transplantation; D012333:RNA, Messenger; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D012333:RNA, Messenger; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D000096743:Interferon gamma Receptor; C494080:Stat1 protein, mouse