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Mesenchymal stromal cells induce distinct myeloid-derived suppressor cells in inflammation
Hyun Ju Lee, … , Hyun Jeong Jeong, Joo Youn Oh
Hyun Ju Lee, … , Hyun Jeong Jeong, Joo Youn Oh
Published May 26, 2020
Citation Information: JCI Insight. 2020;5(12):e136059. https://doi.org/10.1172/jci.insight.136059.
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Research Article Immunology

Mesenchymal stromal cells induce distinct myeloid-derived suppressor cells in inflammation

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Abstract

Mesenchymal stem/stromal cells (MSCs) regulate immunity through myeloid-derived suppressor cells (MDSCs), which are a heterogeneous population of immature myeloid cells with phenotypic and functional diversity. Herein, we identified a distinct subset of MDSCs induced by MSCs in the BM under inflammatory conditions. MSCs directed the differentiation of Ly6Glo BM cells from CD11bhiLy6Chi cells to CD11bmidLy6Cmid cells both in cell contact–independent and –dependent manners upon GM-CSF stimulation in vitro and in mice with experimental autoimmune uveoretinitis (EAU). RNA-Seq indicated that MSC-induced CD11bmidLy6CmidLy6Glo cells had a distinct transcriptome profile from CD11bhiLy6ChiLy6Glo cells. Phenotypic, molecular, and functional analyses showed that CD11bmidLy6CmidLy6Glo cells differed from CD11bhiLy6ChiLy6Glo cells by low expression of MHC class II and costimulatory molecules and proinflammatory cytokines, high production of immunoregulatory molecules, lack of change in response to LPS, and inhibition of T cell proliferation and activation. Consequently, adoptive transfer of MSC-induced CD11bmidLy6CmidLy6Glo cells significantly attenuated the development of EAU in mice. Further mechanistic study revealed that suppression of prostaglandin E2 (PGE2) and HGF secretion in MSCs by siRNA transfection partially reversed the effects of MSCs on MDSC differentiation. Altogether, data demonstrate that MSCs drive the differentiation of BM cells toward CD11bmidLy6CmidLy6Glo MDSCs, in part through HGF and COX-2/PGE2, leading to resolution of ocular autoimmune inflammation.

Authors

Hyun Ju Lee, Jung Hwa Ko, Hyeon Ji Kim, Hyun Jeong Jeong, Joo Youn Oh

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Figure 6

MSC-induced CD11bmidLy6CmidLy6Glo cells inhibit T cell proliferation and Th1 differentiation in a nitric oxide–independent manner.

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MSC-induced CD11bmidLy6CmidLy6Glo cells inhibit T cell proliferation and...
(A) Experimental scheme. CD11bloLy6CloLy6Glo cells, CD11bmidLy6CmidLy6Glo cells, and CD11bhiLy6ChiLy6Glo cells were sorted as in Figure 5A and stimulated with LPS (100 ng/mL) for 18 hours. CD4+ cells were sorted from the spleens of C57BL/6 mice. The sorted CD11bloLy6CloLy6Glo cells, CD11bmidLy6CmidLy6Glo cells, or CD11bhiLy6ChiLy6Glo cells were cocultured in a direct coculture system with CFSE-prelabeled CD4+ cells on anti-CD3– and anti-CD28 antibody–coated plates for 5 days. (B and C) CFSE dilution assay for CD4+ cell proliferation (B) and flow cytometric analysis for IFN-γ+CD4+ cells (C). (D) ELISA for IFN-γ and IL-10 production in the cell-free supernatant of BM cell–CD4+ cell coculture. (E and F) N:(G)-monomethyl-L-arginine (L-NMMA, 5 mM) was added to BM cell–CD4+ cell coculture for the inhibition of nitric oxide synthase (NOS) activity (E), and CD4 cell proliferation and IFN-γ+CD4+ cell differentiation were examined by CFSE assay and flow cytometry (F). Data (mean ± SD) represent 3–8 independent sets of experiments (n = 2–4 in each group per set. Each biological sample was assayed in 3 technical replicates for ELISA). A dot depicts data from 1 biological sample. **P < 0.01, ***P < 0.001, ****P < 0.0001, ns, not significant. One-way ANOVA and Tukey’s multiple-comparison test were used in B, C, D, and F and Mann-Whitney test was used in E.

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