Overexpressing cellular repressor of E1A-stimulated genes protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis by activation of PI3K/Akt |
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Authors: | Jie Deng Yaling Han Chenhui Yan XIaoxiang Tian Jie Tao Jian Kang Shaohua Li |
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Institution: | (1) Xijing Hospital, Fourth Military Medical University, 710032 Xi’an, China;(2) Cardiovascular Research Institute and Department of Cardiology, Shenyang Northern Hospital, 83 Wenhua Road, 110016 Shenyang, China;(3) Department of Surgery, Division of Vascular Surgery, Robert Wood Johnson Medical School-UMDNJ, Piscataway, NJ 08903, USA |
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Abstract: | Bone marrow-derived mesenchymal stem cells (MSCs) have great potential for repair after myocardial infarction. However, poor
viability of transplanted MSCs in the ischemic heart has limited their therapeutic potential. Cellular repressor of E1A-stimulated
genes (CREG) has been identified as a potent inhibitor of apoptosis. The aim of this study was to investigate the anti-apoptotic
effects of CREG on MSCs under hypoxic and serum deprivation (SD) conditions. We also investigated the potential mechanism(s)
that may mediate the actions of CREG. All experiments were performed on rat bone marrow MSCs. Apoptosis was induced by exposure
of cells to hypoxia/SD in a sealed GENbox hypoxic chamber. Effects of CREG were investigated in the absence or presence of
inhibitors that target phosphoinositide 3-kinase (PI3K). We found that the overexpression of CREG markedly protected MSCs
from hypoxia/SD-induced apoptosis through inhibition of the mitochondrial apoptotic pathway, leading to attenuation of caspase-3.
Moreover, CREG enhanced Akt phosphorylation and decreased the expression of p53 in MSCs under hypoxic/SD conditions. The PI3K/Akt
inhibitor LY294002 significantly increased the amount of p53 protein and attenuated the anti-apoptotic effects of CREG on
MSCs. This study indicates that CREG is a novel and potent survival factor for MSCs, therefore, it may be a useful therapeutic
adjunct for transplanting MSCs into damaged heart after myocardial infarction. |
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