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Early growth response-2 signaling mediates immunomodulatory effects of human multipotential stromal cells.

ABSTRACT: While most studies have suggested multipotential stromal cell or mesenchymal stem cell (MSC) therapies are useful for immune-mediated diseases, MSCs' immunomodulatory effects were not entirely reproduced in some studies, indicating the necessity to determine the underlying mechanism of MSCs' effects on immune response regulation to maximize their immunomodulatory effects. We have identified the transcription factor early growth response gene-2 (EGR2) as a novel molecular switch regulating known immunomodulatory molecules in human MSCs. EGR2 binds to the promoter regions of these genes, interleukin-6 (IL6), leukemia inhibitory factor (LIF), indoleamine dioxygenase-1 (IDO1), and cyclooxygenase-2/prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), and siRNA against EGR2 was shown to downregulate these genes and reduce the production of prostaglandin E2, an immunomodulatory mediator produced downstream of COX2/PTGS2. Moreover, EGR2 knockdown restores T-lymphocyte proliferation reduced by MSC coculture. Therefore, EGR2 is a potential target for the optimization of immunomodulatory properties of MSC-based therapies.

SUBMITTER: Barbeau DJ

PROVIDER: S-EPMC3887418 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Early growth response-2 signaling mediates immunomodulatory effects of human multipotential stromal cells.

Barbeau Dominique J DJ La Kiet Tran KT Kim Duk Soo DS Kerpedjieva Svetoslava S SS Shurin Galina V GV Tamama Kenichi K

Stem cells and development 20131005 2

While most studies have suggested multipotential stromal cell or mesenchymal stem cell (MSC) therapies are useful for immune-mediated diseases, MSCs' immunomodulatory effects were not entirely reproduced in some studies, indicating the necessity to determine the underlying mechanism of MSCs' effects on immune response regulation to maximize their immunomodulatory effects. We have identified the transcription factor early growth response gene-2 (EGR2) as a novel molecular switch regulating known ...[more]

PMID: 24007274

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Project description:BACKGROUND:Mesenchymal stromal cells (MSCs), due to their regenerative and immunomodulatory properties, are therapeutically used for diseases, including heart failure. As early gestational-phase embryonic tissues exhibit extraordinary regenerative potential, fetal MSCs exposed to inflammation offer a unique opportunity to evaluate molecular mechanisms underlying preferential healing, and investigate their inherent abilities to communicate with the immune system during development. The principal aim of this study was to evaluate the effects of interferon-? (IFN?) on the immunomodulatory effects of first-trimester human fetal cardiac (hfc)-MSCs. METHODS:hfcMSCs (gestational week 8) were exposed to IFN?, with subsequent analysis of the whole transcriptome, based on RNA sequencing. Exploration of surface-expressed immunoregulatory mediators and modulation of T cell responses were performed by flow cytometry. Presence and activity of soluble mediators were assessed by ELISA or high-performance liquid chromatography. RESULTS:Stimulation of hfcMSCs with IFN? revealed significant transcriptional changes, particularly in respect to the expression of genes belonging to antigen presentation pathways, cell cycle control, and interferon signaling. Expression of immunomodulatory genes and associated functional changes, including indoleamine 2,3-dioxygenase activity, and regulation of T cell activation and proliferation via programmed cell death protein (PD)-1 and its ligands PD-L1 and PD-L2, were significantly upregulated. These immunoregulatory molecules diminished rapidly upon withdrawal of inflammatory stimulus, indicating a high degree of plasticity by hfcMSCs. CONCLUSIONS:To our knowledge, this is the first study performing a systematic evaluation of inflammatory responses and immunoregulatory properties of first-trimester cardiac tissue. In summary, our study demonstrates the dynamic responsiveness of hfcMSCs to inflammatory stimuli. Further understanding as to the immunoregulatory properties of hfcMSCs may be of benefit in the development of novel stromal cell therapeutics for cardiovascular disease.

Dataset Information

Early growth response-2 signaling mediates immunomodulatory effects of human multipotential stromal cells.

Publications

Early growth response-2 signaling mediates immunomodulatory effects of human multipotential stromal cells.

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