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Myocardial ischemic disorders are the leading causes of mortality worldwide, and current therapies only delay progression of these diseases. Traditional stem cell therapies face various impediments, including the typical ethical and immunological problems in clinical application. Recently, induced pluripotent stem (iPS) cells have been shown to offer a novel fascinating route to patient-specific and disease-specific pluripotent cells, without the technical and ethical limitations of somatic cell nuclear transfer method. However, iPS cells' limited viability after transplantation in infarcted microenvironment, and low rate of differentiation into cardiovascular tissues restricts their regenerative capacity. Genetically modified iPS cells with the recently discovered cellular repressor of E1A-stimulated genes (CREG), which inhibits apoptosis and inflammation but enhances differentiation, may resolve these crucial problems. Possible mechanisms may include CREG promotion of angiogenesis by VEGF, suppression of inflammation and resistance of apoptosis via activating PI3K/Akt and blocking p38 MARK signaling, and maintenance of endothelial differentiation conditions. The exact mechanisms that CREG can modulate iPS cells' survival and differentiation remain to be investigated., (Copyright © 2010. Published by Elsevier Ltd.)

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.