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dc.contributor.authorDrago, Deniseen
dc.contributor.authorBasso, Veronicaen
dc.contributor.authorGaude, Edoardoen
dc.contributor.authorVolpe, Giulioen
dc.contributor.authorPeruzzotti Jametti, Lucaen
dc.contributor.authorBachi, Angelaen
dc.contributor.authorMusco, Giovannaen
dc.contributor.authorAndolfo, Annapaolaen
dc.contributor.authorFrezza, Christianen
dc.contributor.authorMondino, Annaen
dc.contributor.authorPluchino, Stefanoen
dc.description.abstract${\bf Background:}$ Neural stem cells (NSCs) display tissue trophic and immune modulatory therapeutic activities after transplantation in central nervous system disorders. The intercellular interplay between stem cells and target immune cells is increased in NSCs exposed to inflammatory cues. Here, we hypothesize that inflammatory cytokine signalling leads to metabolic reprogramming of NSCs regulating some of their immune modulatory effects. ${\bf Methods:}$ NSC lines were prepared from the subventricular zone (SVZ) of 7–12-week-old mice. Whole secretome-based screening and analysis of intracellular small metabolites was performed in NSCs exposed to cocktails of either Th1-like (IFN-γ, 500 U/ml; TNF-α, 200 U/ml; IL-1β, 100 U/ml) or Th2-like (IL-4, IL-5 and IL-13; 10 ng/ml) inflammatory cytokines for 16 h in vitro. Isotopologues distribution of arginine and downstream metabolites was assessed by liquid chromatography/mass spectrometry in NSCs incubated with U-$^{13}$C$_6$ L-arginine in the presence or absence of Th1 or Th2 cocktails (Th1 NSCs or Th2 NSCs). The expression of arginase I and II was investigated in vitro in Th1 NSCs and Th2 NSCs and in vivo in the SVZ of mice with experimental autoimmune encephalomyelitis, as prototypical model of Th1 cell-driven brain inflammatory disease. The effects of the inflammatory cytokine signalling were studied in NSC-lymph node cells (LNC) co-cultures by flow cytometry-based analysis of cell proliferation following pan-arginase inhibition with N$^ω$-hydroxy-nor-arginine (nor-NOHA). ${\bf Results:}$ Cytokine-primed NSCs showed significantly higher anti-proliferative effect in co-cultures vs. control NSCs. Metabolomic analysis of intracellular metabolites revealed alteration of arginine metabolism and increased extracellular arginase I activity in cytokine-primed NSCs. Arginase inhibition by nor-NOHA partly rescued the antiproliferative effects of cytokine-primed NSCs. ${\bf Conclusions:}$ Our work underlines the use of metabolic profiling as hypothesis-generating tools that helps unravelling how stem cell-mediated mechanisms of tissue restoration become affected by local inflammatory responses. Among different therapeutic candidates, we identify arginase signalling as novel metabolic determinant of the NSC-to-immune system communication.
dc.description.sponsorshipThis work has received support from the National Multiple Sclerosis Society (NMSS, partial grants RG-4001-A1), the Italian Multiple Sclerosis Association (AISM, grant 2010/R/31 and grant 2014/PMS/4), the Italian Ministry of Health (GR08-7), the European Research Council (ERC) under the ERC-2010-StG Grant agreement n° 260511-SEM_SEM and the UK Regenerative Medicine Platform Acellular hub (Partnership award RG69889) and core support grant from the Wellcome Trust and MRC to the Wellcome Trust–Medical Research Council Cambridge Stem Cell Institute. LPJ was supported by a Wellcome Trust Research Training Fellowship (RG79423).
dc.publisherBioMed Central
dc.rightsAttribution 4.0 International*
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.subjectneural stem cellsen
dc.subjectimmune modulationen
dc.subjectlymph node cellsen
dc.subjectarginase Ien
dc.titleMetabolic determinants of the immune modulatory function of neural stem cellsen
dc.description.versionThis is the final version of the article. It first appeared from BioMed Central via
prism.publicationNameJournal of Neuroinflammationen
dc.contributor.orcidPeruzzotti Jametti, Luca [0000-0002-9396-5607]
dc.contributor.orcidFrezza, Christian [0000-0002-3293-7397]
dc.contributor.orcidPluchino, Stefano [0000-0002-6267-9472]
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idMedical Research Council (MC_UU_12022/6)
pubs.funder-project-idEuropean Research Council (260511)
cam.orpheus.successThu Jan 30 12:58:09 GMT 2020 - The item has an open VoR version.*

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International