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EPO protects mesenchymal stem cells from hyperglycaemic injury via activation of the Akt/FoxO3a pathway

Cui, Jinjin, Liu, Xiaohong, Zhang, Zhuoqi, Xuan, Yongli, Liu, Xinxin, Zhang, Fengyun
Life sciences 2019 v.222 pp. 158-167
Western blotting, angiogenesis, beta-galactosidase, cardiovascular diseases, cell viability, chronic exposure, enzyme-linked immunosorbent assay, erythropoietin, flow cytometry, human umbilical vein endothelial cells, hyperglycemia, inflammation, males, mesenchymal stromal cells, rats, secretion, signal transduction, somatomedins, staining, tumor necrosis factor-alpha, vascular endothelial growth factors
Mesenchymal stem cell (MSC)-based therapies have demonstrated positive outcomes for treating cardiovascular disease. However, the proliferative ability of MSCs decreases during chronic exposure to hyperglycaemia; their ability to contribute to endogenous injury repair is thus reduced. Erythropoietin (EPO) was recently reported to protect against hyperglycaemia-related injury in various cells and may be a good candidate for enhancing MSC functions under hyperglycaemic conditions.Bone marrow-derived MSCs were isolated from male donor rats weighing 60–80 g. The roles of EPO in regulating cell viability, senescence, angiogenesis and inflammation were investigated using the Cell Counting Kit-8 (CCK-8) assay and 5-ethynyl-2′-deoxyuridine (EdU) assays; senescence-associated β-galactosidase (SA-β-gal) staining; VEGF, HGF, IGF, bFGF ELISAs and TNF-α ELISA, respectively. ROS production was measured by flow cytometry. The expression levels of Akt, forkhead box class O3a (FoxO3a) and VEGF proteins in MSCs were analysed by western blotting. Matrigel was used for tube formation assays.The results of the current study showed that EPO has beneficial effects on MSCs exposed to hyperglycaemia by promoting proliferation, inhibiting senescence and the release of pro-inflammatory factors, increasing the secretion of proangiogenic cytokines, and enhancing the ability of MSCs to stimulate tube formation among human umbilical vein endothelial cells (HUVECs). In addition, the beneficial effects of EPO may result from the activation of the Akt/FoxO3a signalling pathway.Our study demonstrates for the first time that EPO protects MSCs from hyperglycaemia-induced damage by targeting the Akt/FoxO3a signalling pathway.