title: Overexpression of cellular repressor of E1A-stimulated genes inhibits TNF-α-induced apoptosis via NF-κB in mesenchymal stem cells.
abstract: Bone marrow-derived mesenchymal stem cells (MSCs) show great potential for therapeutic repair after myocardial infarction. However, poor viability of transplanted MSCs in the ischemic heart has limited their use. Cellular repressor of E1A-stimulated genes (CREG) has been identified as a potent inhibitor of apoptosis. This study therefore aimed to determine if rat bone marrow MSCs transfected with CREG-were able to effectively resist apoptosis induced by inflammatory mediators, and to demonstrate the mechanism of CREG action. Apoptosis was determined by flow cytometric and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assays. The pathways mediating these apoptotic effects were investigated by Western blotting. Overexpression of CREG markedly protected MSCs from tumor necrosis factor-α (TNF-α) induced apoptosis by 50% after 10 h, through inhibition of the death-receptor-mediated apoptotic pathway, leading to attenuation of caspase-8 and caspase-3. Moreover, CREG resisted the serine phosphorylation of IκBα and prevented the nuclear translocation of the transcription factor nuclear factor-κB (NF-κB) under TNF-α stimulation. Treatment of cells with the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) significantly increased the transcription of pro-apoptosis proteins (p53 and Fas) by NF-κB, and attenuated the anti-apoptotic effects of CREG on MSCs. The results of this study indicate that CREG acts as a novel and potent survival factor in MSCs, and may therefore be a useful therapeutic adjunct for transplanting MSCs into the damaged heart after myocardial infarction.
authors.affiliation: Xijing Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Cheng-Fei
authors.initials: CF
authors.lastname: Peng
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Han
authors.lastname: Jie-Deng
authors.forename: Cheng-Hui
authors.initials: CH
authors.lastname: Yan
authors.lastname: Jian-Kang
authors.lastname: Bo-Luan
authors.lastname: Jie-Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D015536:Down-Regulation; D020672:I-kappa B Proteins / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors
chemical_list: C495367:Creg1 protein, rat; D020672:I-kappa B Proteins; D016328:NF-kappa B; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53