Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 37, Issue 1, Pages 117-130Publisher
KARGER
DOI: 10.1159/000430338
Keywords
Mesenchymal stem cells (MSCs); Regulatory B cells (Breg); Immunomodulatory; CXCL12/SDF-1 alpha
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Funding
- Shanghai Academic Leaders' Program of the Health System [XBR2011038]
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Background/Aims: Mesenchymal stem cells (MSCs) possess immunomodulatory properties on a diverse array of immune cell lineages, including regulatory T and B cells (Tregs and Bregs, respectively). However, their specific effects and mechanisms underlying induction of Bregs remain unclear. The immune regulatory function of MSCs is exerted through both cell-cell contact and the release of soluble factors. The main objective of this study was to examine the role of the SDF-1-CXCR4/CXCR7 axis in the secretory action of MSCs, and potential effects on the immunoregulatory function of these cells. Methods: MSCs were isolated from mouse bone marrow and characterized according to their multilineage differentiation potential and their surface antigen expression. CD19(+) B cells purified from mice splenocytes were co-cultured with MSCs at various ratios in the presence of LPS and alpha CD40. After 4 days, intracellular IL-10 production and cell surface CD1d and CD5 expression by CD19(+) B cells were determined using flow cytometry, and the secretion of IL-10, IL-6, IgM, and IgG were assessed with ELISA. MSCs were treated with different concentrations of stromal derived factor-1 alpha (SDF-1 alpha) stimuli or transiently overexpressed with CXCR7. and their cell viability and immune regulatory effects of MSCs on Bregs were assessed. Results: MSCs induced IL-10-producing regulatory B cells and primarily stimulated the CD1d(+)CD(+)B cell subset of IL-10(+)Breg cells to express IL-10. IL-10, IL-6, and IgM secretion were additionally induced by MSCs. The CXCR7 pathway was required for MSC viability and the production of paracrine factors under SDF-1 alpha culture condition. Low concentrations of SDF-1 alpha promoted the immunomodulatory effect of MSCs, leading to a further increase in IL-10-producing regulatory B cells and IL-10 secretion. In contrast, high concentrations of SDF-1 alpha inhibited MSCs induction of IL-10(+)Breg cells. Notably, CXCR7 overexpression in MSCs reversed the inhibitory effect of high concentrations of SDF-1 alpha and promoted the immunomodulatory effect of these cells. Conclusion: MSCs induce IL-10(+)Breg cells, which contribute to the generation of an immunosuppressive environment. SDF-1 alpha and its receptor, CXCR7 play important roles in the immunomodulatory function of MSCs by regulating their paracrine actions. Copyright (C) 2015 S Karger AG, Basel
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