Characterization of Urine Stem Cell-Derived Extracellular Vesicles Reveals B Cell Stimulating Cargo

Abstract

Elucidation of the biological functions of extracellular vesicles (EVs) and their potential roles in physiological and pathological processes is an expanding field of research. In this study, we characterized USC–derived EVs and studied their capacity to modulate the human immune response in vitro. We found that the USC–derived EVs are a heterogeneous population, ranging in size from that of micro–vesicles (150 nm–1 μm) down to that of exosomes (60–150 nm). Regarding their immunomodulatory functions, we found that upon isolation, the EVs (60–150 nm) induced B cell proliferation and IgM antibody secretion. Analysis of the EV contents unexpectedly revealed the presence of BAFF, APRIL, IL–6, and CD40L, all known to play a central role in B cell stimulation, differentiation, and humoral immunity. In regard to their effect on T cell functions, they resembled the function of mesenchymal stem cell (MSC)–derived EVs previously described, suppressing T cell response to activation. The finding that USC–derived EVs transport a potent bioactive cargo opens the door to a novel therapeutic avenue for boosting B cell responses in immunodeficiency or cancer.

Extracellular Vesicles from Hypoxic Pretreated Urine-Derived Stem Cells Enhance the Proliferation and Migration of Chondrocytes by Delivering miR-26a-5p

“…Through flow cytometry analysis, we found that the isolated USCs expressed some traditional MSC-surface markers, such as CD44 and CD90. However, unlike the previous studies, 26 , 51 the isolated USCs were weakly positively for CD73 and CD105. The difference in immunophenotype between different USCs may be attributed to the cell heterogeneity of USCs.…”

Cellular and Molecular Targets of Extracellular Vesicles from Mesenchymal Stem/Stromal Cells in Rheumatoid Arthritis

“… 45 In addition, EVs from human urine MSCs (U-MSCs) reduce T-cell proliferation in response to anti-CD3/CD28 stimulation. 46 EVs can also increase the apoptosis of T cells, as reported for mouse BM-MSC EVs. 47 Besides, BM-MSC EVs inhibit the activation of mouse splenocytes mediated by Toll-like receptor 4 (TLR4) and T-cell receptor leading to the inhibition of nuclear factor κ-light-­chain-enhancer of activated B cells (NF-κB) and nuclear factor of activated T cells 1.…”

Isolation, Culture and Comprehensive Characterization of Biological Properties of Human Urine-Derived Stem Cells

“…Similarly, a recent study carried out by Cao et al also revealed that alveolar bone-derived stem cells secreted mainly IL-6 and MCP-1, and thus, at least partially, explained mechanisms behind their immunosuppressive capacity [37]. Intriguingly, IL-6 was also de-scribed as a part of extracellular vesicles derived from the UDSCs [29]. Moreover, these vesicles carried multiple bioactive molecules which could stimulate B-Lymphocytes and simultaneously suppress the function of T-Lymphocytes.…”

“…Paradoxically, UDSCs secretome has not been sufficiently characterized. Several studies described immunomodulatory effect of exosomes derived of UDSCs [29][30][31]. Here, we performed the analysis of the secretion of the basic cytokines and chemokines under standard in vitro conditions.…”

“…Our data revealed significantly increased secretion of 3 particular molecules-IL-6, IL-8 and MCP-1. In general, IL-6 plays essential role in anti-inflammatory effects of MSC by stimulating local lymphocytes [11,29]. Moreover, IL-6 stimulated MSCs can in turn activate Treg cells, which are known for their immunosuppressive capacity and immune system modulation.…”