Journal
MOLECULAR CELL
Volume 56, Issue 2, Pages 193-204Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2014.08.020
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Funding
- National Multiple Sclerosis Society (NMSS) [RG-4001-A1]
- Italian Multiple Sclerosis Foundation (FISM) [RG 2010/R/31]
- Italian Ministry of Health [GR08/7]
- European Research Council (ERC) [RG 260511-SEM_SEM]
- European Community (EC) [RG 280772-iONE]
- Evelyn Trust [RG 69865]
- Australian Research Council/University of Queensland [FF0561986]
- Australian National Health and Medical Research Council Australia [631668]
- Fundacao para a Ciencia e a Tecnologia (FCT) [SFRH/BD/15899/2005]
- FEBS
- Human Frontiers Science Program
- BBSRC [BB/J01589X/1]
- Biotechnology and Biological Sciences Research Council [BB/J01589X/1] Funding Source: researchfish
- BBSRC [BB/J01589X/1] Funding Source: UKRI
- Fundação para a Ciência e a Tecnologia [SFRH/BD/15899/2005] Funding Source: FCT
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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.
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