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Open Access 01-12-2016 | Research

Metabolic determinants of the immune modulatory function of neural stem cells

Authors: Denise Drago, Veronica Basso, Edoardo Gaude, Giulio Volpe, Luca Peruzzotti-Jametti, Angela Bachi, Giovanna Musco, Annapaola Andolfo, Christian Frezza, Anna Mondino, Stefano Pluchino

Published in: Journal of Neuroinflammation | Issue 1/2016

Abstract

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.

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-¹³C₆ 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).

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 anti-proliferative effects of cytokine-primed NSCs.

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.

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Title: Metabolic determinants of the immune modulatory function of neural stem cells
Authors: Denise Drago
Veronica Basso
Edoardo Gaude
Giulio Volpe
Luca Peruzzotti-Jametti
Angela Bachi
Giovanna Musco
Annapaola Andolfo
Christian Frezza
Anna Mondino
Stefano Pluchino
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0667-7

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Metabolic determinants of the immune modulatory function of neural stem cells

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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