Mesenchymal Stromal Cells Protect Against Caspase 3-Mediated Apoptosis of CD19⁺Peripheral B Cells Through Contact-Dependent Upregulation of VEGF

Abstract

The immune suppressive and anti-inflammatory capabilities of bone marrow-derived mesenchymal stromal cells (MSCs) represent an innovative new tool in regenerative medicine and immune regulation. The potent immune suppressive ability of MSC over T cells, dendritic cells, and natural killer cells has been extensively characterized, however, the effect of MSC on B cell function has not yet been clarified. In this study, the direct effect of MSC on peripheral blood B cell function is defined and the mechanism utilized by MSC in enhancing B cell survival in vitro identified. Human MSC supported the activation, proliferation, and survival of purified CD19(+) B cells through a cell contact-dependent mechanism. These effects were not mediated through B cell activating factor or notch signaling. However, cell contact between MSC and B cells resulted in increased production of vascular endothelial growth factor (VEGF) by MSC facilitating AKT phosphorylation within the B cell and inhibiting caspase 3-mediated apoptosis. Blocking studies demonstrated that this cell contact-dependent effect was not dependent on signaling through CXCR4-CXCL12 or through the epidermal growth factor receptor (EGFR). These results suggest that direct cell contact between MSC and B cells supports B cell viability and function, suggesting that MSC may not represent a suitable therapy for B cell-mediated disease.

Infusion of umbilical cord mesenchymal stem cells alleviates symptoms of ankylosing spondylitis

“…Due to their multi-differentiation capacity, MSCs may induce the synthesis of proteoglycans and restore disc structure and may also suppress B cell function (44). In vitro studies have demonstrated that MSCs may prevent B cells from activating, proliferating and differentiating into immunoglobulin (Ig)-producing cells (45,46). Furthermore, MSCs may be a potential treatment for cardiovascular diseases, including ischemic heart disease and peripheral artery disease (47).…”

Mesenchymal Stem Cell Derived Extracellular Vesicles: A Role in Hematopoietic Transplantation?

“…Conversely, a recent study by Healy et al reports that human BM-MSCs support the activation, proliferation, and survival of purified CD19+ peripheral B-cells through a cell contact-dependent mechanism [30]. As reported by different studies, MSCs exert an inhibitor effect on NK cells [24,31,32].…”

Interaction between Mesenchymal Stem Cells and B-Cells

“…According to Healy et al , MSCs can inhibit the caspase 3-mediated apoptosis of peripheral CD19+ B-cells through direct cell–cell interaction. This inhibition is dependent on the MSC-induced upregulation of vascular endothelial growth factor (VEGF), and a p-PKBA blocking experiment showed that the signal transmission following cell–cell contact is not dependent on CXCR12-CXCL4 or epidermal growth factor receptor (EGFR) [ 53 ]. ASCs can also secrete an unknown soluble factor that promotes the chemotaxis and mobility of B-cells.…”