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Association of TNF-? with impaired migration capacity of mesenchymal stem cells in patients with systemic lupus erythematosus.

ABSTRACT: Previous studies indicated that bone marrow mesenchymal stem cells (BMSCs) from patients with systemic lupus erythematosus (SLE) exhibited impaired capacities of proliferation, differentiation, and immune modulation. Considering that migration capacity is important for the exertion of BMSCs functions, the defects in migration might contribute to BMSCs dysfunction in SLE patients. In this study, we showed that the migration capacity of SLE BMSCs was remarkably impaired in comparison with those of healthy controls. Increased tumor necrosis factor ? (TNF-?) in SLE serum significantly inhibited the migration capacity and in vivo homing capacity of SLE BMSCs via a specific TNF receptor I (TNFRI) manner, in which decreased HGF mRNA production caused by the activation of I kappa B kinase beta (IKK-?) pathway is partially involved. To our knowledge, this is the first report to discuss the possible mechanisms for impaired migration of BMSCs in SLE patients. Our results suggest that inhibition of TNF-? pathway might be helpful for accelerating BMSCs migration to the inflammatory microenvironment in SLE patients, thereby having a potential role in SLE treatment.

SUBMITTER: Geng L

PROVIDER: S-EPMC4265382 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Association of TNF-α with impaired migration capacity of mesenchymal stem cells in patients with systemic lupus erythematosus.

Geng Linyu L Li Xia X Feng Xuebing X Zhang Jiyun J Wang Dandan D Chen Jinyun J Liu Rui R Chen Haifeng H Sun Lingyun L

Journal of immunology research 20141124

Previous studies indicated that bone marrow mesenchymal stem cells (BMSCs) from patients with systemic lupus erythematosus (SLE) exhibited impaired capacities of proliferation, differentiation, and immune modulation. Considering that migration capacity is important for the exertion of BMSCs functions, the defects in migration might contribute to BMSCs dysfunction in SLE patients. In this study, we showed that the migration capacity of SLE BMSCs was remarkably impaired in comparison with those of ...[more]

PMID: 25762184

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Project description:Systemic lupus erythematosus (SLE) is a polymorphic, multisystemic autoimmune disease that causes multiorgan damage in which cellular communication occurs through the involvement of autoantibodies directed against autoantigen production. Mesenchymal stem cells (MSCs), which have strong protective and immunomodulatory abilities, are obtained not only from bone marrow but also from medical waste such as adipose tissue and umbilical cord tissue and have been recognized as a promising tool for the treatment of various autoimmune diseases and inflammatory disorders. This meta-analysis is aimed at assessing whether MSCs can become a new treatment for SLE with good efficacy and safety. Based on predetermined criteria, a bibliographical search was performed from January 1, 2000, to July 31, 2019, by searching the following databases: ISI Web of Science, Embase, PubMed, the Cochrane Library, and the Chinese Biomedical Literature Database (CBM). Eligible studies and data were identified. Statistical analysis was conducted to assess the efficacy (proteinuria, systemic lupus erythematosus disease activity index (SLEDAI), Scr, BUN, albumin, C3, and C4) and safety (rate of adverse events) of MSCs for SLE using Cochrane Review Manager Version 5.3. Ten studies fulfilled the inclusion criteria and were eligible for this meta-analysis, which comprised 8 prospective or retrospective case series and four randomized controlled trails (RCTs) studies. In the RCT, the results indicated that the MSC group had lower proteinuria than the control group at 3 months and 6 months and the MSC group displayed a lower SLEDAI than the control group at 2 months and 6 months. Furthermore, the MSC group showed a lower rate of adverse events than the control group (OR = 0.26, 95% CI: 0.07, 0.89, P = 0.03). In the case series trials, the results indicated that the MSC group had lower proteinuria at 1 month, 2 months, 3 months, 4 months, 6 months, and 12 months. In conclusion, MSCs might be a promising therapeutic agent for patients with SLE.

Project description:Background and objectiveUmbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown immunoregulation of various immune cells. The aim of this study was to investigate the mechanism of UC MSCs in the regulation of peripheral regulatory T cells (Treg) and T helper 17 (Th17) cells in patients with systemic lupus erythematosus (SLE).MethodsThirty patients with active SLE, refractory to conventional therapies, were given UC MSCs infusions. The percentages of peripheral blood CD4+CD25+Foxp3+ regulatory T cells (Treg) and CD3+CD8-IL17A+ Th17 cells and the mean fluorescence intensities (MFI) of Foxp3 and IL-17 were measured at 1 week, 1 month, 3 months, 6 months, and 12 months after MSCs transplantation (MSCT). Serum cytokines, including transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-17A were detected using ELISA. Peripheral blood mononuclear cells from patients were collected and co-cultured with UC MSCs at ratios of 1:1, 10:1, and 50:1, respectively, for 72 h to detect the proportions of Treg and Th17 cells and the MFIs of Foxp3 and IL-17 were determined by flow cytometry. The cytokines in the supernatant solution were detected using ELISA. Inhibitors targeting TGF-β, IL-6, indoleamine 2,3-dioxygenase (IDO), and prostaglandin E2 were added to the co-culture system, and the percentages of Treg and Th17 cells were observed.ResultsThe percentage of peripheral Treg and Foxp3 MFI increased 1 week, 1 month, and 3 months after UC MSCs transplantation, while the Th17 proportion and MFI of IL-17 decreased 3 months, 6 months, and 12 months after the treatment, along with an increase in serum TGF-β at 1 week, 3 months, and 12 months and a decrease in serum TNF-α beginning at 1 week. There were no alterations in serums IL-6 and IL-17A before or after MSCT. In vitro studies showed that the UC MSCs dose-dependently up-regulated peripheral Treg proportion in SLE patients, which was not depended on cell-cell contact. However, the down-regulation of Th17 cells was not dose-dependently and also not depended on cell-cell contact. Supernatant TGF-β and IL-6 levels significantly increased, TNF-α significantly decreased, but IL-17A had no change after the co-culture. The addition of anti-TGF-β antibody significantly abrogated the up-regulation of Treg, and the addition of PGE2 inhibitor significantly abrogated the down-regulation of Th17 cells. Both anti-IL-6 antibody and IDO inhibitor had no effects on Treg and Th17 cells.ConclusionsUC MSCs up-regulate Treg and down-regulate Th17 cells through the regulation of TGF-β and PGE2 in lupus patients.

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Association of TNF-? with impaired migration capacity of mesenchymal stem cells in patients with systemic lupus erythematosus.

Publications

Association of TNF-α with impaired migration capacity of mesenchymal stem cells in patients with systemic lupus erythematosus.

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