Jeong Sin-Gu, Cho Goang-Won
Department of Biology, College of Natural Science, Chosun University, Gwangju, Korea; Department of Life Science, BK21-Plus Research Team for Bioactive Control Technology, Chosun University, Gwangju, Korea.
Cell Biochem Funct. 2015 Jan;33(1):37-43. doi: 10.1002/cbf.3084. Epub 2014 Dec 16.
Engraft cells are often exposed to oxidative stress and inflammation; therefore, any factor that can provide the stem cells resistance to these stresses may yield better efficacy in stem cell therapy. Studies indicate that histone deacetylase (HDACs) inhibitors alleviate damage induced by oxidative stress. In this study, we investigated whether regulation of reactive oxygen species (ROS) occurs through the HDAC inhibitor trichostatin A (TSA) in human bone marrow-mesenchymal stem cells (hBM-MSCs). Intracellular ROS levels increased following exposure to hydrogen peroxide (H2 O2 ), and were suppressed by TSA treatment. Levels of the antioxidant enzyme superoxide dismutase 2 (SOD2) increased following treatment with 200 nM TSA and to a lesser level at 1-5 μM TSA. Cell protective effects against oxidative stress were significantly increased in TSA-MSCs after treatment with low doses of TSA (50-500 nM) and decreased with high doses of TSA (5-10 μM). Consistent results were obtained with immunoblot analysis for caspase3. Investigation of Forkhead box O1 (FOXO1), superoxide dismutase 2 (SOD2), and p53 levels to determine intracellular signaling by TSA in oxidative stress-induced MSCs demonstrated that expression of phosphorylated-FOXO1 and phosphorylated-SOD2 decreased in H2 O2 -treated MSCs while levels of p53 increased. These effects were reversed by the treatment of 200 nM TSA. These results suggest that the main function of ROS modulation by TSA is activated through SOD2 and FOXO1. Thus, optimal treatment with TSA may protect hBM-MSCs against oxidative stress.
植入细胞经常暴露于氧化应激和炎症中；因此，任何能够使干细胞抵抗这些应激的因素都可能在干细胞治疗中产生更好的疗效。研究表明，组蛋白脱乙酰酶（HDACs）抑制剂可减轻氧化应激诱导的损伤。在本研究中，我们调查了在人骨髓间充质干细胞（hBM-MSCs）中，组蛋白脱乙酰酶抑制剂曲古抑菌素A（TSA）是否通过调节活性氧（ROS）发挥作用。暴露于过氧化氢（H2O2）后，细胞内ROS水平升高，而TSA处理可抑制其升高。用200 nM TSA处理后，抗氧化酶超氧化物歧化酶2（SOD2）的水平升高，在1-5 μM TSA处理时升高程度较小。低剂量TSA（50-500 nM）处理后的TSA-MSCs对氧化应激的细胞保护作用显著增强，而高剂量TSA（5-10 μM）处理则使其降低。对caspase3的免疫印迹分析也得到了一致的结果。通过检测叉头框O1（FOXO1）、超氧化物歧化酶2（SOD2）和p53水平来确定TSA在氧化应激诱导的间充质干细胞中的细胞内信号传导，结果表明，在H2O2处理的间充质干细胞中，磷酸化-FOXO1和磷酸化-SOD2的表达降低，而p53水平升高。200 nM TSA处理可逆转这些效应。这些结果表明，TSA调节ROS的主要功能是通过SOD2和FOXO1激活的。因此，TSA的最佳处理可能保护hBM-MSCs免受氧化应激。
