Interleukin-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro

Elena Redondo-Castro, Catriona Cunningham, Jonjo Miller, Licia Martuscelli, Sarah Aoulad-Ali, Nancy J. Rothwell, Cay M. Kielty, Stuart M. Allan, Emmanuel Pinteaux*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

157 Citations (Scopus)
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Abstract

Background
Inflammation is a key contributor to central nervous system (CNS) injury such as stroke, and is a major target for therapeutic intervention. Effective treatments for CNS injuries are limited and applicable to only a minority of patients. Stem cell-based therapies are increasingly considered for the treatment of CNS disease, because they can be used as in-situ regulators of inflammation, and improve tissue repair and recovery. One promising option is the use of bone marrow-derived mesenchymal stem cells (MSCs), which can secrete anti-inflammatory and trophic factors, can migrate towards inflamed and injured sites or can be implanted locally. Here we tested the hypothesis that pre-treatment with inflammatory cytokines can prime MSCs towards an anti-inflammatory and pro-trophic phenotype in vitro.
Methods
Human MSCs from three different donors were cultured in vitro and treated with inflammatory mediators as follows: interleukin (IL)-1α, IL-1β, tumour necrosis factor alpha (TNF-α) or interferon-γ. After 24 h of treatment, cell supernatants were analysed by ELISA for expression of granulocyte-colony stimulating factor (G-CSF), IL-10, brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), IL-1 receptor antagonist (IL-1Ra) and vascular endothelial growth factor (VEGF). To confirm the anti-inflammatory potential of MSCs, immortalised mouse microglial BV2 cells were treated with bacterial lipopolysaccharide (LPS) and exposed to conditioned media (CM) of naïve or IL-1-primed MSCs, and levels of secreted microglial-derived inflammatory mediators including TNF-α, IL-10, G-CSF and IL-6 were measured by ELISA.
Results
Unstimulated MSCs constitutively expressed anti-inflammatory cytokines and trophic factors (IL-10, VEGF, BDNF, G-CSF, NGF and IL-1Ra). MSCs primed with IL-1α or IL-1β showed increased secretion of G-CSF, which was blocked by IL-1Ra. Furthermore, LPS-treated BV2 cells secreted less inflammatory and apoptotic markers, and showed increased secretion of the anti-inflammatory IL-10 in response to treatment with CM of IL-1-primed MSCs compared with CM of unprimed MSCs.
Conclusions
Our results demonstrate that priming MSCs with IL-1 increases expression of trophic factor G-CSF through an IL-1 receptor type 1 (IL-1R1) mechanism, and induces a reduction in the secretion of inflammatory mediators in LPS-activated microglial cells. The results therefore support the potential use of preconditioning treatments of stem cells in future therapies.
Original languageEnglish
Article number79
Number of pages11
JournalStem cell research & therapy
Volume8
DOIs
Publication statusPublished - 17 Apr 2017
Externally publishedYes

Bibliographical note

The authors would like to acknowledge the assistance of Rebecca Holley (Wellcome Trust Centre for Cell-Matrix Research, UK Centre for Tissue Engineering) and Gareth Howell (Flow Cytometry Facility within the Manchester Collaborative Centre for Inflammation Research). They thank Swedish Orphan Biovitrum AB for providing the Kineret® used in these studies.
The work was supported by funds from the Stroke Association (UK), the Engineering and Physical Sciences Research Council (EPSRC), the Medical Research Council (MRC), the Centre for Doctoral Training in Regenerative Medicine studentship grant EP/L014904/1 and the Manchester Regenerative Medicine Network (MaRM).

Keywords

  • Stroke
  • Human mesenchymal stem cells
  • Cytokines
  • Priming
  • Bone marrow-derived stromal cells
  • Interleukin-1

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