Mesenchymal stromal cells induce distinct myeloid-derived suppressor cells in inflammation
Hyun Ju Lee, Jung Hwa Ko, Hyeon Ji Kim, Hyun Jeong Jeong, Joo Youn Oh
Hyun Ju Lee, Jung Hwa Ko, Hyeon Ji Kim, Hyun Jeong Jeong, Joo Youn Oh
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Research Article Immunology

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

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 5

Inflammatory activation status of MSC-induced CD11bmidLy6CmidLy6Glo cells in comparison with CD11bhiLy6ChiLy6Glo cells or CD11bloLy6CloLy6Glo cells.

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Inflammatory activation status of MSC-induced CD11bmidLy6CmidLy6Glo cell...
(A) CD11bloLy6CloLy6Glo cells were sorted from BM cells that had been cultured for 5 days without MSCs in the absence of GM-CSF. CD11bhiLy6ChiLy6Glo cells were isolated from BM cells cultured for 5 days under GM-CSF incubation (40 ng/mL) but without MSC coculture. CD11bmidLy6CmidLy6Glo cells were sorted from GM-CSF–stimulated, MSC-cocultured BM cells. The secreted levels of IL-10 and TNF-α were measured in the cell-free supernatant of each cell culture before and after LPS stimulation (100 ng/mL) for 18 hours. Scale bar: 50 μm. Data (mean ± SD) are from 3 independent sets of experiments (n = 3–4 in each group per set. Each biological sample was assayed in 3 technical replicates). A dot depicts data from 1 biological sample. ****P < 0.0001 by 1-way ANOVA and Tukey’s multiple-comparison test. (B and C) Heatmaps of RNA-Seq on CD11bhiLy6ChiLy6Glo cells, CD11bmidLy6CmidLy6Glo cells, and CD11bloLy6CloLy6Glo cells. The first column (blue box) depicts changes in the gene expression levels in CD11bhiLy6ChiLy6Glo cells relative to CD11bloLy6CloLy6Glo cells. The second column (red box) depicts the gene expression changes in CD11bmidLy6CmidLy6Glo cells relative to CD11bloLy6CloLy6Glo cells. The genes related to inflammation and immune response are shown in B, and the genes related to cell differentiation and immune response are shown in C. The whole data are deposited in ArrayExpress (accession E-MTAB-8975).