Induction of Regulatory B-Cells by Mesenchymal Stem Cells is Affected by SDF-1α-CXCR7

Abstract

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 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. Conclusion: 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.

Mesenchymal Stem and Progenitor Cells in Normal and Dysplastic Hematopoiesis—Masters of Survival and Clonality?

“…These include, e.g., PGE2, TGFβ, IL2, IL6, hepatocyte growth factor (HGF), indoleamine 2,3-dioxygenase (IDO) [ 399 ], human leukocyte antigen (HLA), IL 1 receptor antagonist (IL1RA), CCL2, macrophage colony stimulating factor (M-CSF), and MSPC-secreted exosomes as paracrine mediators of MSPC immunosuppressive function ( Figure 4 ) [ 389 , 407 , 409 , 413 , 416 , 425 , 430 , 442 , 450 , 452 , 462 , 463 , 464 , 465 , 466 ]. The immunosuppressive cytokine IL10 is not produced by MSPCs themselves, but they induce other cell types to do this, in part via heme oxygenase-1 [ 443 , 460 , 467 ].…”

Recent Developments in Cellular Immunotherapy for HSCT-Associated Complications

“…Results from in vitro experiments show that while MSCs impair the proliferation and terminal differentiation of B cells (252) they have also been shown to stimulate antibody secretion (253). More recently, data have emerged which suggests that MSCs can promote the induction of regulatory B cells (Breg) (254). Neutrophils are an important mediator of the innate response and MSCs have been shown to enhance their survival through an IL-6-mediated mechanism, concomitant with the downregulation of reactive oxygen species, thereby conserving the pool of neutrophils primed to respond rapidly to infection (255).…”

Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression

“…Recently, VEGF secretion by MSCs has been shown to have an important role in the survival of B cells through the activation of the AKT signaling pathway that inhibits the expression of caspase-3 [69]. MSCs directly promote the development of CD19 + CD24 high CD38 high IL-10-secreting regulatory B cells through the chemokine stromal derived factor-1 α (SDF-1 α ) and its receptor, CXCR7, which contribute to the generation of an immunosuppressive environment [70, 71]. Finally, in arthritis, we have shown that MSCs inhibit plasmoblasts generation in vivo in CIA through the expression of the IL-1 receptor antagonist (IL-1RA) on MSCs [18].…”