PMID- 28412968 OWN - NLM STAT- MEDLINE DCOM- 20171127 LR - 20181202 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 8 IP - 1 DP - 2017 Apr 17 TI - Interleukin-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro. PG - 79 LID - 10.1186/s13287-017-0531-4 [doi] LID - 79 AB - 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)-1alpha, IL-1beta, tumour necrosis factor alpha (TNF-alpha) or interferon-gamma. 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 naive or IL-1-primed MSCs, and levels of secreted microglial-derived inflammatory mediators including TNF-alpha, 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-1alpha or IL-1beta 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. FAU - Redondo-Castro, Elena AU - Redondo-Castro E AD - Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. FAU - Cunningham, Catriona AU - Cunningham C AD - Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. FAU - Miller, Jonjo AU - Miller J AD - Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. FAU - Martuscelli, Licia AU - Martuscelli L AD - Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. FAU - Aoulad-Ali, Sarah AU - Aoulad-Ali S AD - Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. FAU - Rothwell, Nancy J AU - Rothwell NJ AD - Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. FAU - Kielty, Cay M AU - Kielty CM AD - Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. AD - Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. FAU - Allan, Stuart M AU - Allan SM AD - Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. FAU - Pinteaux, Emmanuel AU - Pinteaux E AD - Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. emmanuel.pinteaux@manchester.ac.uk. LA - eng GR - Medical Research Council/United Kingdom PT - Journal Article DEP - 20170417 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 RN - 0 (Anti-Inflammatory Agents) RN - 0 (Biomarkers) RN - 0 (Culture Media, Conditioned) RN - 0 (Interleukin-1alpha) RN - 0 (Interleukin-1beta) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 0 (Nerve Growth Factors) RN - 0 (Tumor Necrosis Factor-alpha) RN - 143011-72-7 (Granulocyte Colony-Stimulating Factor) SB - IM MH - Adult MH - Animals MH - Anti-Inflammatory Agents/*pharmacology MH - Biomarkers/metabolism MH - Culture Media, Conditioned/pharmacology MH - Female MH - Granulocyte Colony-Stimulating Factor/pharmacology MH - Humans MH - Interleukin-1alpha/*pharmacology MH - Interleukin-1beta/*pharmacology MH - Interleukin-6/metabolism MH - Lipopolysaccharides/pharmacology MH - Male MH - Mesenchymal Stem Cells/*cytology/drug effects/metabolism MH - Mice MH - Microglia/cytology/drug effects MH - Nerve Growth Factors/pharmacology MH - Phenotype MH - Tumor Necrosis Factor-alpha/metabolism MH - Young Adult PMC - PMC5393041 OTO - NOTNLM OT - Bone marrow-derived stromal cells OT - Cytokines OT - Human mesenchymal stem cells OT - Interleukin-1 OT - Priming OT - Stroke EDAT- 2017/04/18 06:00 MHDA- 2017/11/29 06:00 PMCR- 2017/04/17 CRDT- 2017/04/18 06:00 PHST- 2016/11/01 00:00 [received] PHST- 2017/03/08 00:00 [accepted] PHST- 2017/03/01 00:00 [revised] PHST- 2017/04/18 06:00 [entrez] PHST- 2017/04/18 06:00 [pubmed] PHST- 2017/11/29 06:00 [medline] PHST- 2017/04/17 00:00 [pmc-release] AID - 10.1186/s13287-017-0531-4 [pii] AID - 531 [pii] AID - 10.1186/s13287-017-0531-4 [doi] PST - epublish SO - Stem Cell Res Ther. 2017 Apr 17;8(1):79. doi: 10.1186/s13287-017-0531-4.