Extracellular Vesicles from Neural Stem Cells Transfer IFN-γ via Ifngr1 to Activate Stat1 Signaling in Target Cells

被引：260

作者：

Cossetti, Chiara ^{[1
,2
,3
]}

Iraci, Nunzio ^{[1
,2
,3
]}

Mercer, Tim R. ^{[4
]}

Leonardi, Tommaso ^{[1
,2
,3
,5
]}

Alpi, Emanuele ^{[6
]}

Drago, Denise ^{[6
]}

Alfaro-Cervello, Clara ^{[1
,2
,3
]}

Saini, Harpreet K. ^{[5
]}

Davis, Matthew P. ^{[5
]}

Schaeffer, Julia ^{[1
,2
,3
]}

Vega, Beatriz ^{[1
,2
,3
]}

Stefanini, Matilde ^{[1
,2
,3
]}

Zhao, CongJian ^{[7
]}

Muller, Werner ^{[8
]}

Manuel Garcia-Verdugo, Jose ^{[9
]}

Mathivanan, Suresh ^{[10
]}

Bachi, Angela ^{[6
]}

Enright, Anton J. ^{[5
]}

Mattick, John S. ^{[11
]}

Pluchino, Stefano ^{[1
,2
,3
]}

机构：

[1] Univ Cambridge, Dept Clin Neurosci, John van Geest Ctr Brain Repair, Cambridge CB2 0PY, England

[2] Univ Cambridge, NIHR Biomed Res Ctr, Cambridge CB2 0PY, England

[3] Wellcome Trust Med Res Council Stem Cell Inst, Cambridge, England

[4] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia

[5] EMBL European Bioinformat Inst, Cambridge CB10 1SD, England

[6] Ist Sci San Raffaele, Div Genet & Cell Biol, Biomol Mass Spectrometry Unit, I-20132 Milan, Italy

[7] Third Mil Med Univ, Southwest Eye Hosp, Southwest Hosp, Chongqing 400038, Peoples R China

[8] Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, England

[9] Univ Valencia, Inst Cavanilles, Dept Neurobiol Comparada, Valencia 46980, Spain

[10] La Trobe Univ, La Trobe Inst Mol Sci, Dept Biochem, Bundoora, Vic 3086, Australia

[11] Garvan Inst, Darlinghurst, NSW 2010, Australia

来源：

MOLECULAR CELL | 2014年 / 56卷 / 02期

基金：

欧洲研究理事会; 澳大利亚研究理事会; 英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

INTERCELLULAR TRANSFER; EXOSOMES; BRAIN; RECEPTOR; RNA; REGENERATION; ASSOCIATION; PLASTICITY; BINDING;

D O I：

10.1016/j.molcel.2014.08.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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. Wedescribed induction of interferon gamma (IFN-gamma) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-gamma 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-gamma/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-gamma/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system.

引用

页码：193 / 204

页数：12

共 44 条

[11] Targeted disruption of the mouse STAT1 results in compromised innate immunity to viral disease [J].