Immunomodulatory effect of human bone marrow‐derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients

Pedrosa, M. Figueroa; Gomes, Joana; Laranjeira, Pires; Duarte, Cátia; Pedreiro, Susana; Antunes, Brígida; Ribeiro, Tania; Santos, Filipe Neves dos; Martinho, António; Fardilha, Margarida; Domingues, M. Rosário M.; Abecasis, Manuel M.; Silva, José António Pereira da; Paiva, Artur

doi:10.1002/term.2958

Cited by 35 publications

(27 citation statements)

References 47 publications

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“…Mesenchymal stem cells (MSCs) have extensive immunomodulatory effects, such as inhibiting T cell proliferation, activation and cytokine production; however, the detailed mechanism by which MSCs regulate T cells remains poorly defined [15,16]. In the present study, we found that the percentage of CD4+CD25+Foxp3+ cells in the CD4+ T cell population was significantly decreased, while the percentage of CD4+CD3+RORrt+ cells was significantly increased after a coculture with MSCs.…”

Section: Discussionmentioning

confidence: 46%

Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro

Chen

Liu

et al. 2020

Stem Cell Res Ther

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Introduction: Mesenchymal stem cells (MSCs) exert immunomodulatory functions by inducing the development and differentiation of naive T cells into T cells with an anti-inflammatory regulatory T cell (Treg) phenotype. Our previous study showed that hepatocyte growth factor (HGF) secreted by MSCs had immunomodulatory effects in the context of lipopolysaccharide (LPS) stimulation. We hypothesized that HGF is a key factor in the MSC-mediated regulation of the T helper 17 (Th17) cell/regulatory T (Treg) cell balance. Methods: We investigated the effects of MSCs on the differentiation of CD4+ T cells and the functions of Th17/ Treg cells in response to LPS stimulation by performing in vitro coculture experiments. MSCs were added to the upper chambers of cell culture inserts, and CD4+ T cells were plated in the lower chambers, followed by treatment with LPS or an anti-HGF antibody. Th17 (CD4+CD3+RORrt+) and Treg (CD4+CD25+Foxp3+) cell frequencies were analysed by flow cytometry, and the expression of Th17 cell-and Treg cell-related cytokines in the CD4+ T cells or culture medium was measured by quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Neutrophil functions were determined by flow cytometry after a coculture with Th17/Treg cells.Results: The percentage of CD4+CD25+Foxp3+ cells was significantly increased in the CD4+ T cell population, while the percentage of CD4+CD3+RORrt+ cells was significantly decreased after MSC coculture. However, the MSC-induced effect was significantly inhibited by the anti-HGF antibody (p < 0.05). Furthermore, MSCs significantly inhibited the CD4+ T cell expression of IL-17 and IL-6 but increased the expression of IL-10 (p < 0.05 or p < 0.01); these effects were inhibited by the anti-HGF antibody (p < 0.05). In addition, CD4+ T cells cocultured with MSCs significantly inhibited neutrophil phagocytic and oxidative burst activities (p < 0.05 or p < 0.01); however, these MSCinduced effects were inhibited by the anti-HGF antibody (p < 0.05).Conclusion: These data suggested that MSCs induced the conversion of fully differentiated Th17 cells into functional Treg cells and thereby modulated the Th17/Treg cell balance in the CD4+ T cell population, which was partly attributed to HGF secreted by the MSCs.

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Section: Discussionmentioning

confidence: 46%

Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro

Chen

Liu

et al. 2020

Stem Cell Res Ther

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“…Inflammatory cytokines including tumor necrosis factor- (TNF-) α , interleukin- (IL-) 1 β , IL-6, and IL-17 play a critical role in the pathogenesis of RA. Specifically, TNF- α , IL-1 β , and IL-17 induce RA synovitis with the promotion of vasospasm and cause bone destruction in late-stage synovitis [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Rheumatoid Arthritis Using Bark, Leaf, and Male Flower Extracts of Eucommia ulmoides

Xing

Wang

Yan

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Eucommia ulmoides Oliv., a native Chinese plant species, has been used as a traditional Chinese medicine formulation to treat rheumatoid arthritis (RA), strengthen bones and muscles, and lower blood pressure. Various parts of this plant such as the bark, leaves, and flowers have been found to have anti-inflammatory properties. E. ulmoides has potential applications as a therapeutic agent against bone disorders, which were investigated in this study. In vitro, RA joint fibroblast-like synoviocytes (RA-FLS) were treated with different concentrations (0, 25, 50, 100, 200, 400, 800, and 1000 μg/mL) of E. ulmoides bark, leaf, and male flower alcoholic extracts (EB, EL, and EF, respectively) to determine their potential cytotoxicity. Tumor necrosis factor- (TNF-) α and nitric oxide (NO) levels in RA-FLS were quantified using enzyme-linked immunosorbent assay (ELISA). Furthermore, collagen-induced arthritis (CIA) rats were treated with EB, EL, EF, Tripterygium wilfordii polyglycoside (TG) or the normal control (Nor), and then ankle joint pathology, bone morphology, and serum and spleen inflammatory cytokine levels were evaluated. The results showed that, in RA-FLS, EB, EL, and EF were not cytotoxic; EB and EF reduced TNF-α supernatant levels; and EB, EL, and EF reduced NO levels. The results of in vivo experiments showed that EB, EL, and EF alleviated ankle swelling and joint inflammation, while all extracts diminished inflammatory cell infiltration, pannus and bone destruction, and bone erosion. All tested extracts inhibited interleukin- (IL-) 6, IL-17, and TNF-α mRNA in the spleen of CIA rats, while EB most effectively reduced osteoclasts and inhibited bone erosion. EF showed the most obvious inhibition of inflammatory factors and pannus. Thus, EB, EL, and EF may alleviate bone destruction by inhibiting inflammation.

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“…Rashedi et al[ 47 ] have reported that MSCs can either increase the level of Treg cells by directly interacting with Tregs through the Notch signaling pathway or indirectly induce CD4 + lymphocytes to differentiate into Treg cells[ 47 ]. In addition, bone marrow-derived MSCs can also inhibit the production of inflammatory cytokines by T cells in RA[ 48 ]. The significant anti-inflammatory role of MSCs on T cells is mainly dependent on hindering the nuclear factor-κB signaling pathway[ 49 ], which has been well recognized as the pivotal downstream signaling pathway involved in rheumatic disease pathogenesis[ 50 ].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles: Potential roles in rheumatic diseases

Yang

Liu

Wang

et al. 2020

WJSC

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BACKGROUND Mesenchymal stem cells (MSCs) have been widely investigated in rheumatic disease due to their immunomodulatory and regenerative properties. Recently, mounting studies have implicated the therapeutic potency of MSCs mostly due to the bioactive factors they produce. Extracellular vesicles (EVs) derived from MSCs have been identified as a promising cell-free therapy due to low immunogenicity. Rheumatic disease, primarily including rheumatoid arthritis and osteoarthritis, is a group of diseases in which immune dysregulation and chronic progressive inflammation lead to irreversible joint damage. Targeting MSCs and MSC-derived EVs may be a more effective and promising therapeutic strategy for rheumatic diseases. AIM To evaluate the potential therapeutic effectiveness of MSCs and EVs generated from MSCs in rheumatic diseases. METHODS PubMed was searched for the relevant literature using corresponding search terms alone or in combination. Papers published in English language from January 1999 to February 2020 were considered. Preliminary screening of papers concerning analysis of "immunomodulatory function" or "regenerative function" by scrutinizing the titles and abstracts of the literature, excluded the papers not related to the subject of the article. Some other related studies were obtained by manually retrieving the reference lists of papers that comply with the selection criteria, and these studies were screened to meet the final selection and exclusion criteria. RESULTS Eighty-six papers were ultimately selected for analysis. After analysis of the literature, it was found that both MSCs and EVs generated from MSCs have great potential in multiple rheumatic diseases, such as rheumatoid arthritis and osteoarthritis, in repair and regeneration of tissues, inhibition of inflammatory response, and regulation of body immunity via promoting chondrogenesis, regulating innate and adaptive immune cells, and regulating the secretion of inflammatory factors. But EVs from MSCs exhibit much more advantages over MSCs, which may represent another promising cell-free restorative strategy. Targeting MSCs and MSC-derived EVs may be a more efficient treatment for patients with rheumatic diseases. CONCLUSION The enormous potential of MSCs and EVs from MSCs in immunomodulation and tissue regeneration offers a new idea for the treatment of rheumatism. However, more in-depth exploration is needed before their clinical application.

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Immunomodulatory effect of human bone marrow‐derived mesenchymal stromal/stem cells on peripheral blood T cells from rheumatoid arthritis patients

Cited by 35 publications

References 47 publications

Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro

Mesenchymal stem cells regulate the Th17/Treg cell balance partly through hepatocyte growth factor in vitro

Inhibition of Rheumatoid Arthritis Using Bark, Leaf, and Male Flower Extracts of Eucommia ulmoides

Mesenchymal stem cells and mesenchymal stem cell-derived extracellular vesicles: Potential roles in rheumatic diseases

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