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Interferon-? and Tumor Necrosis Factor-? Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype.

ABSTRACT: Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-?) and tumor necrosis factor alpha (TNF-?), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-? and IFN-? stimulated MSCs expressed distinct sets of proinflammatory factors. The combination of IFN-? and TNF-? was synergistic and induced a transcriptome most similar to that found in MSCs stimulated with activated T cells and similar to that found in the inflamed tumor microenvironment; a Th1 phenotype with the expression of the immunosuppressive factors IL-4, IL-10, CD274/PD-L1 and indoleamine 2,3 dioxygenase (IDO). Single cell qRT-PCR analysis showed that the combination of IFN-? and TNF-? polarized uniformly to this phenotype. The combination of IFN-? and TNF-? results in the synergist uniform polarization of MSCs toward a primarily Th1 phenotype. The stimulation of MSCs by IFN-? and TNF-? released from activated tumor infiltrating T cells is likely responsible for the production of many factors that characterize the tumor microenvironment.

SUBMITTER: Jin P

PROVIDER: S-EPMC4876328 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype.

Jin Ping P Zhao Yuanlong Y Liu Hui H Chen Jinguo J Ren Jiaqiang J Jin Jianjian J Bedognetti Davide D Liu Shutong S Wang Ena E Marincola Francesco F Stroncek David D

Scientific reports 20160523

Activated T cells polarize mesenchymal stromal cells (MSCs) to a proinflammatory Th1 phenotype which likely has an important role in amplifying the immune response in the tumor microenvironment. We investigated the role of interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), two factors produced by activated T cells, in MSC polarization. Gene expression and culture supernatant analysis showed that TNF-α and IFN-γ stimulated MSCs expressed distinct sets of proinflammatory factors. Th ...[more]

PMID: 27211104

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Project description:BackgroundMesenchymal stromal cells (MSCs) are attractive for cell-based therapies ranging from regenerative medicine and tissue engineering to immunomodulation. However, clinical efficacy is variable and it is unclear how the phenotypes defining bone marrow (BM)-derived MSCs as well as donor characteristics affect their functional properties.MethodsBM-MSCs were isolated from 53 (25 female, 28 male; age: 13 to 80 years) donors and analyzed by: (1) phenotype using flow cytometry and cell size measurement; (2) in vitro growth kinetics using population doubling time; (3) colony formation capacity and telomerase activity; and (4) function by in vitro differentiation capacity, suppression of T cell proliferation, cytokines and trophic factors secretion, and hormone and growth factor receptor expression. Additionally, expression of Oct4, Nanog, Prdm14 and SOX2 mRNA was compared to pluripotent stem cells.ResultsBM-MSCs from younger donors showed increased expression of MCAM, VCAM-1, ALCAM, PDGFR?, PDL-1, Thy1 and CD71, and led to lower IL-6 production when co-cultured with activated T cells. Female BM-MSCs showed increased expression of IFN-?R1 and IL-6?, and were more potent in T cell proliferation suppression. High-clonogenic BM-MSCs were smaller, divided more rapidly and were more frequent in BM-MSC preparations from younger female donors. CD10, ?1integrin, HCAM, CD71, VCAM-1, IFN-?R1, MCAM, ALCAM, LNGFR and HLA ABC were correlated to BM-MSC preparations with high clonogenic potential and expression of IFN-?R1, MCAM and HLA ABC was associated with rapid growth of BM-MSCs. The mesodermal differentiation capacity of BM-MSCs was unaffected by donor age or gender but was affected by phenotype (CD10, IFN-?R1, GD2). BM-MSCs from female and male donors expressed androgen receptor and FGFR3, and secreted VEGF-A, HGF, LIF, Angiopoietin-1, basic fibroblast growth factor (bFGF) and NGFB. HGF secretion correlated negatively to the expression of CD71, CD140b and Galectin 1. The expression of Oct4, Nanog and Prdm14 mRNA in BM-MSCs was much lower compared to pluripotent stem cells and was not related to donor age or gender. Prdm14 mRNA expression correlated positively to the clonogenic potential of BM-MSCs.ConclusionsBy identifying donor-related effects and assigning phenotypes of BM-MSC preparations to functional properties, we provide useful tools for assay development and production for clinical applications of BM-MSC preparations.

Dataset Information

Interferon-? and Tumor Necrosis Factor-? Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype.

Publications

Interferon-γ and Tumor Necrosis Factor-α Polarize Bone Marrow Stromal Cells Uniformly to a Th1 Phenotype.

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