title: Induction of Regulatory B-Cells by Mesenchymal Stem Cells is Affected by SDF-1α-CXCR7.
abstract: OBJECTIVE
  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 αCD40. 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-1α (SDF-1α) 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(+)CD5(+)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-1α culture condition. Low concentrations of SDF-1α 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-1α inhibited MSCs induction of IL-10(+)Breg cells. Notably, CXCR7 overexpression in MSCs reversed the inhibitory effect of high concentrations of SDF-1α and promoted the immunomodulatory effect of these cells.
  
  
  CONCLUSIONS
  MSCs induce IL-10(+)Breg cells, which contribute to the generation of an immunosuppressive environment. SDF-1α and its receptor, CXCR7 play important roles in the immunomodulatory function of MSCs by regulating their paracrine actions.
authors: Department of Urology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Yan
authors: Y
authors: Qin
authors: Zhihua
authors: Z
authors: Zhou
authors: Fang
authors: F
authors: Zhang
authors: Yong
authors: Y
authors: Wang
authors: Bing
authors: B
authors: Shen
authors: Yong
authors: Y
authors: Liu
authors: Yifeng
authors: Y
authors: Guo
authors: Yu
authors: Y
authors: Fan
authors: Jianxin
authors: J
authors: Qiu
mesh_terms: D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000378:metabolism*; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage / Q000502:physiology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018920:Coculture Techniques; D007378:Interleukins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D054387:Receptors, CXCR / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D054377:Chemokine CXCL12; C501897:Cmkor1 protein, mouse; D007378:Interleukins; D054387:Receptors, CXCR