Overexpressing cellular repressor of E1A-stimulated genes protects mesenchymal stem cells against hypoxia- and serum deprivation-induced apoptosis by activation of PI3K/Akt.
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.
Deng
Jie
J
Xijing Hospital, Fourth Military Medical University, Xi'an, China. jie.deng@hotmail.com
Han
Yaling
Y
Yan
Chenhui
C
Tian
Xiaoxiang
X
Tao
Jie
J
Kang
Jian
J
Li
Shaohua
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D016895:Culture Media, Serum-Free; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; C495367:Creg1 protein, rat