Caballano-Infantes Estefanía, Díaz Irene, Hitos Ana Belén, Cahuana Gladys Margot, Martínez-Ruiz Antonio, Soria-Juan Bárbara, Rodríguez-Griñolo Rosario, Hmadcha Abdelkrim, Martín Franz, Soria Bernat, Tejedo Juan R, Bedoya Francisco Javier
Department of Regeneration and Cell Therapy, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, 41013 Seville, Spain.
Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain.
Antioxidants (Basel). 2021 Sep 2;10(9):1408. doi: 10.3390/antiox10091408.
The optimization of conditions to promote the stemness of pluripotent cells in vitro is instrumental for their use in advanced therapies. We show here that exposure of human iPSCs and human ESCs to low concentrations of the chemical NO donor DETA/NO leads to stabilization of hypoxia-inducible factors (HIF-1α and HIF-2α) under normoxia, with this effect being dependent on diminished Pro 402 hydroxylation and decreased degradation by the proteasome. Moreover, the master genes of pluripotency, NANOG and OCT-4, were upregulated. NO also induces a shift in the metabolic profile of PSCs, with an increased expression of hypoxia response genes in glycolysis. Furthermore, a reduction in the mitochondrial membrane potential with lower oxygen consumption and increased expression of mitochondrial fusion regulators, such as DRP1, was observed. The results reported here indicate that NO mimics hypoxia response in human PSCs and enhances their stemness properties when cultured under normoxic conditions.
优化体外促进多能干细胞干性的条件对于其在先进疗法中的应用至关重要。我们在此表明，将人诱导多能干细胞（iPSCs）和人胚胎干细胞（ESCs）暴露于低浓度的化学一氧化氮供体DETA/NO下，会导致在常氧条件下缺氧诱导因子（HIF-1α和HIF-2α）的稳定，这种效应依赖于Pro 402羟基化的减少和蛋白酶体降解的降低。此外，多能性的主控基因NANOG和OCT-4被上调。NO还会诱导多能干细胞代谢谱的转变，糖酵解中缺氧反应基因的表达增加。此外，观察到线粒体膜电位降低，氧气消耗减少，以及线粒体融合调节因子（如DRP1）的表达增加。此处报道的结果表明，NO在人多能干细胞中模拟缺氧反应，并在常氧条件下培养时增强其干性特性。
