Metabolic determinants of the immune modulatory function of neural stem cells
Authors
Drago, Denise
Basso, Veronica
Gaude, Edoardo
Volpe, Giulio
Bachi, Angela
Musco, Giovanna
Andolfo, Annapaola
Mondino, Anna
Publication Date
2016-09-02Journal Title
Journal of Neuroinflammation
ISSN
1742-2094
Publisher
BioMed Central
Volume
13
Number
232
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Drago, D., Basso, V., Gaude, E., Volpe, G., Peruzzotti Jametti, L., Bachi, A., Musco, G., et al. (2016). Metabolic determinants of the immune modulatory function of neural stem cells. Journal of Neuroinflammation, 13 (232)https://doi.org/10.1186/s12974-016-0667-7
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.
Keywords
metabolomics, neural stem cells, immune modulation, lymph node cells, arginase I
Sponsorship
This 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).
Funder references
MRC (MC_PC_12009)
Medical Research Council (MC_UU_12022/6)
European Research Council (260511)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1186/s12974-016-0667-7
This record's URL: https://www.repository.cam.ac.uk/handle/1810/260093
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
Recommended or similar items
The following licence files are associated with this item: