The Immunosuppressive Effect of Mesenchymal Stromal Cells on B Lymphocytes is Mediated by Membrane Vesicles

Abstract

The immunomodulatory properties of mesenchymal stromal cells are the subject of increasing interest and of widening clinical applications, but the reproducibility of their effects is controversial and the underlying mechanisms have not been fully clarified. We investigated the transfer of membrane vesicles, a recently recognized pathway of intercellular communication, as possible mediator of the interaction between mesenchymal stromal cells and B lymphocytes. Mesenchymal stromal cells exhibited a strong dose-dependent inhibition of B-cell proliferation and differentiation in a CpG-stimulated peripheral blood mononuclear cell coculture system. We observed that these effects could be fully reproduced by membrane vesicles isolated from mesenchymal stromal cell culture supernatants in a dose-dependent fashion. Next, we evaluated the localization of fluorescently labeled membrane vesicles within specific cell subtypes both by flow cytometry and by confocal microscopy analysis. Membrane vesicles were found to be associated with stimulated B lymphocytes, but not with other cell phenotypes (T lymphocytes, dendritic cells, natural killer cells), in peripheral blood mononuclear cell culture. These results suggest that membrane vesicles derived from mesenchymal stromal cells are the conveyors of the immunosuppressive effect on B lymphocytes. These particles should be further evaluated as immunosuppressive agents in place of the parent cells, with possible advantages in term of standardization, safety, and feasibility.

Opposite Prognostic Significance of Cellular and Serum Circulating MicroRNA-150 in Patients with Chronic Lymphocytic Leukemia

“…To elucidate if circulating microRNA-150 was encapsulated in exosomes, in microvesicles or in protein/lipid complexes, 15 CLL serums were centrifuged at 20,000g (to pellet microvesicles) and subsequently at 150,000g (to pellet exosomes) for 1 h at 4°C as previously described (25,26). Uncentrifuged, microvesicle-depleted and exosome-depleted sera were processed as described above to detect microRNA levels.…”

The secretome of mesenchymal stromal cells: Role of extracellular vesicles in immunomodulation

“…These authors observed a dose-dependent inhibitory effect of MSC-EVs on B-cell proliferation, differentiation and production of IgM, IgG and IgA, in a CpG-stimulated peripheral blood mononuclear cell culture system [68]. Moreover, it has been shown that MSC-EVs are internalized only in a subset of activated B lymphocytes CD19+/CD86+ [68].…”

“…The effect of EVs obtained from human bone marrow MSCs on B lymphocytes has been investigated by Budoni et al [68]. These authors observed a dose-dependent inhibitory effect of MSC-EVs on B-cell proliferation, differentiation and production of IgM, IgG and IgA, in a CpG-stimulated peripheral blood mononuclear cell culture system [68].…”

MSCS in Scenarios of Infection and Inflammation: Focus on Neonatal Diseases

“…In animal and in vitro studies, MSC-derived extracellular vesicles restored Th1/ Th2 balance and induced generation of Tregs, implementing the regulatory component of the adaptive immune system [77,78]. A dose-dependent inhibitory effect of MSC-derived extracellular vesicles on B-cell proliferation, differentiation and Ig production has been reported [58]. In a mouse model of severe refractory asthma, MSC-derived extracellular vesicles were as potent as the MSCs themselves in mitigating allergic airway inflammation [79].…”

“…1). Some studies have suggested that MSCs can also inhibit B cell activation, proliferation, differentiation and chemotactic responses [58], although knowledge regarding MSC-mediated modulation of B cells is still limited (Fig. 1).…”