Dataset Information

TNF-? Induced the Enhanced Apoptosis of Mesenchymal Stem Cells in Ankylosing Spondylitis by Overexpressing TRAIL-R2.

ABSTRACT: Ankylosing spondylitis (AS) is an autoimmune disease with unknown etiology. Dysregulated mesenchymal stem cells (MSCs) apoptosis may contribute to the pathogenesis of autoimmune diseases. However, apoptosis of MSCs from patients with AS (ASMSCs) has not been investigated yet. The present study aims to assess the apoptosis of bone marrow-derived ASMSCs and to investigate the underlying mechanisms of altered ASMSCs apoptosis. We successfully induced the apoptosis of ASMSCs and MSCs from healthy donors (HDMSCs) using the combination of tumor necrosis factor alpha (TNF-?) and cycloheximide (CHX). We found that ASMSCs treated with TNF-? and CHX showed higher apoptosis levels compared to HDMSCs. During apoptosis, ASMSCs expressed significantly more TRAIL-R2, which activated both the death receptor pathway and mitochondria pathway by increasing the expression of FADD, cleaved caspase-8, cytosolic cytochrome C, and cleaved caspase-3. Inhibiting TRAIL-R2 expression using shRNA eliminated the apoptosis differences between HDMSCs and ASMSCs by partially reducing ASMSCs apoptosis but minimally affecting that of HDMSCs. Furthermore, the expression of FADD, cleaved caspase-8, cytosolic cytochrome C, and cleaved caspase-3 were comparable between HDMSCs and ASMSCs after TRAIL-R2 inhibition. These results indicated that increased TRAIL-R2 expression results in enhanced ASMSCs apoptosis and may contribute to AS pathogenesis.

SUBMITTER: Liu Z

PROVIDER: S-EPMC5274669 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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TNF-<i>α</i> Induced the Enhanced Apoptosis of Mesenchymal Stem Cells in Ankylosing Spondylitis by Overexpressing TRAIL-R2.

Liu Zhenhua Z Gao Liangbin L Wang Peng P Xie Zhongyu Z Cen Shuizhong S Li Yuxi Y Wu Xiaohua X Wang Le L Su Hongjun H Deng Wen W Wang Shan S Li Deng D Li Jinteng J Ouyang Yi Y Wu Yanfeng Y Shen Huiyong H

Stem cells international 20170115

Ankylosing spondylitis (AS) is an autoimmune disease with unknown etiology. Dysregulated mesenchymal stem cells (MSCs) apoptosis may contribute to the pathogenesis of autoimmune diseases. However, apoptosis of MSCs from patients with AS (ASMSCs) has not been investigated yet. The present study aims to assess the apoptosis of bone marrow-derived ASMSCs and to investigate the underlying mechanisms of altered ASMSCs apoptosis. We successfully induced the apoptosis of ASMSCs and MSCs from healthy do ...[more]

PMID: 28182106

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Project description:Adult neurons, which are terminally differentiated cells, demonstrate substantial radioresistance. In contrast, human neural stem cells (NSC), which have a significant proliferative capacity, are highly sensitive to ionizing radiation. Cranial irradiation that is widely used for treatment of brain tumors may induce death of NSC and further cause substantial cognitive deficits such as impairing learning and memory. The main goal of our study was to determine a mechanism of NSC radiosensitivity. We observed a constitutive high-level expression of TRAIL-R2 in human NSC. On the other hand, ionizing radiation through generation of reactive oxygen species targeted cell signaling pathways and dramatically changed the pattern of gene expression, including upregulation of TRAIL. A significant increase of endogenous expression and secretion of TRAIL could induce autocrine/paracrine stimulation of the TRAIL-R2-mediated signaling cascade with activation of caspase-3-driven apoptosis. Furthermore, paracrine stimulation could initiate bystander response of non-targeted NSC that is driven by death ligands produced by directly irradiated NSC. Experiments with media transfer from directly irradiated NSC to non-targeted (bystander) NSC confirmed a role of secreted TRAIL for induction of a death signaling cascade in non-targeted NSC. Subsequently, TRAIL production through elimination of bystander TRAIL-R-positive NSC might substantially restrict a final yield of differentiating young neurons. Radiation-induced TRAIL-mediated apoptosis could be partially suppressed by anti-TRAIL antibody added to the cell media. Interestingly, direct gamma-irradiation of SK-N-SH human neuroblastoma cells using clinical doses (2-5 Gy) resulted in low levels of apoptosis in cancer cells that was accompanied however by induction of a strong bystander response in non-targeted NSC. Numerous protective mechanisms were involved in the maintenance of radioresistance of neuroblastoma cells, including constitutive PI3K-AKT over-activation and endogenous synthesis of TGFβ1. Specific blockage of these survival pathways was accompanied by a dramatic increase in radiosensitivity of neuroblastoma cells. Intercellular communication between cancer cells and NSC could potentially be involved in amplification of cancer pathology in the brain.

Dataset Information

TNF-? Induced the Enhanced Apoptosis of Mesenchymal Stem Cells in Ankylosing Spondylitis by Overexpressing TRAIL-R2.

Publications

TNF-<i>α</i> Induced the Enhanced Apoptosis of Mesenchymal Stem Cells in Ankylosing Spondylitis by Overexpressing TRAIL-R2.

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