1 Department of Obstetrics, Gynecology & Reproductive Sciences, University of Maryland School of Medicine , Baltimore, Maryland.
2 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine , Baltimore, Maryland.
Stem Cells Dev. 2018 Jun 1;27(11):745-755. doi: 10.1089/scd.2017.0203.
Maternal diabetes induces neural tube defects by suppressing neurogenesis in the developing neuroepithelium. Our recent study further revealed that high glucose inhibited embryonic stem cell differentiation into neural lineage cells. However, the mechanism whereby high glucose suppresses neural differentiation is unclear. To investigate whether high glucose-induced oxidative stress and endoplasmic reticulum (ER) stress lead to the inhibition of neural differentiation, the effect of high glucose on neural stem cell (the C17.2 cell line) differentiation was examined. Neural stem cells were cultured in normal glucose (5 mM) or high glucose (25 mM) differentiation medium for 3, 5, and 7 days. High glucose suppressed neural stem cell differentiation by significantly decreasing the expression of the neuron marker Tuj1 and the glial cell marker GFAP and the numbers of Tuj1 and GFAP cells. The antioxidant enzyme superoxide dismutase mimetic Tempol reversed high glucose-decreased Tuj1 and GFAP expression and restored the numbers of neurons and glial cells differentiated from neural stem cells. Hydrogen peroxide treatment imitated the inhibitory effect of high glucose on neural stem cell differentiation. Both high glucose and hydrogen peroxide triggered ER stress, whereas Tempol blocked high glucose-induced ER stress. The ER stress inhibitor, 4-phenylbutyrate, abolished the inhibition of high glucose or hydrogen peroxide on neural stem cell differentiation. Thus, oxidative stress and its resultant ER stress mediate the inhibitory effect of high glucose on neural stem cell differentiation.
母体糖尿病通过抑制发育中的神经上皮中的神经发生诱导神经管缺陷。我们最近的研究进一步表明，高葡萄糖抑制胚胎干细胞分化为神经谱系细胞。然而，高葡萄糖抑制神经分化的机制尚不清楚。为了研究高葡萄糖诱导的氧化应激和内质网（ER）应激是否导致神经分化抑制，我们检查了高葡萄糖对神经干细胞（C17.2 细胞系）分化的影响。神经干细胞在正常葡萄糖（5mM）或高葡萄糖（25mM）分化培养基中培养 3、5 和 7 天。高葡萄糖通过显著降低神经元标志物 Tuj1 和神经胶质细胞标志物 GFAP 的表达以及 Tuj1 和 GFAP 细胞的数量来抑制神经干细胞分化。抗氧化酶超氧化物歧化酶模拟物 Tempol 逆转了高葡萄糖降低的 Tuj1 和 GFAP 表达，并恢复了神经干细胞分化的神经元和神经胶质细胞数量。过氧化氢处理模拟了高葡萄糖对神经干细胞分化的抑制作用。高葡萄糖和过氧化氢均引发 ER 应激，而 Tempol 阻断了高葡萄糖诱导的 ER 应激。ER 应激抑制剂 4-苯基丁酸消除了高葡萄糖或过氧化氢对神经干细胞分化的抑制作用。因此，氧化应激及其导致的 ER 应激介导了高葡萄糖对神经干细胞分化的抑制作用。
