Histone deacetylase inhibitors epigenetically promote reparative events in primary dental pulp cells
Histone deacetylase inhibitors epigenetically promote reparative events in primary dental pulp cells
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DOI：
10.1016/j.yexcr.2013.02.022
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发表时间：
2013-06-10
影响因子：
3.7
通讯作者：
Cooper, Paul R.
中科院分区：
文献类型：
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作者：
Duncan, Henry F.;Smith, Anthony J.;Cooper, Paul R.
对细胞应用组蛋白脱乙酰酶抑制剂 (HDACi) 可在表观遗传上改变其染色质结构并诱导转录和细胞修复事件。本研究调查了两种 HDACi、丙戊酸 (WA) 和曲古抑菌素 A (TSA) 在诱导原代牙髓细胞 (DPC) 培养物中修复相关反应中的应用。流式细胞术证明 TSA（100 nM、400 nM）显着提高细胞活力。尽管细胞生长分析显示较高浓度的 WA (> 0.5 mM) 和 TSA (>50 nM) 具有显着的抗增殖作用，但 HDACi 均不具有细胞毒性。虽然高内涵分析表明 HDACi 不会显着诱导 caspase-3 或 p21 活性，但 WA (3 mM、5 mM) 在 48 小时时 p53 表达增加。 HDACi 暴露剂量依赖性地诱导每个细胞矿化至平台水平（VPA0.125 mM 和 TSA-25 nM），并伴随第 5 天（DMP-1、BMP-2/-4、Nestin）和 10 天（DSPP、BMP-2/-4）时矿化/牙本质相关基因表达的增加。两种 HDACi 在一定浓度范围内均在第 10 天和 14 天显着刺激骨桥蛋白和 BMP-2 蛋白表达，进一步支持了 HDACi 促进分化的能力。与转化的 DPC 相比，HDACi 对原代细胞发挥不同的作用，并促进矿化和分化事件，而没有细胞毒性作用。这些新数据现在凸显了在活体牙髓治疗中应用低浓度 HDACi 的修复牙科潜力 (C) 2013 Elsevier Inc. 保留所有权利。
Application of histone deacetylase inhibitors (HDACi) to cells epigenetically alters their chromatin structure and induces transcriptional and cellular reparative events. This study investigated the application of two HDACi, valproic acid (WA) and trichostatin A (TSA) on the induction of repair-associated responses in primary dental pulp cell (DPC) cultures. Flow cytometry demonstrated that TSA (100 nM, 400 nM) significantly increased cell viability. Neither HDACi was cytotoxic, although cell growth analysis revealed significant anti-proliferative effects at higher concentrations for WA ( > 0.5 mM) and TSA (>50 nM). While high-content-analysis demonstrated that HDACi did not significantly induce caspase-3 or p21 activity, p53-expression was increased by WA (3 mM, 5 mM) at 48 h. HDACi-exposure induced mineralization per cell dose-dependently to a plateau level (VPA0.125 mM and TSA-25 nM) with accompanying increases in mineralization/dentinogenic-associated gene expression at 5 days (DMP-1, BMP-2/-4, Nestin) and 10 days (DSPP, BMP-2/-4). Both HDACis, at a range of concentrations, significantly stimulated osteopontin and BMP-2 protein expression at 10 and 14 days further supporting the ability of HDACi to promote differentiation. HDACi exert different effects on primary compared with transformed DPCs and promote mineralization and differentiation events without cytotoxic effects. These novel data now highlight the potential in restorative dentistry for applying low concentrations of HDACi in vital pulp treatment (C) 2013 Elsevier Inc. All rights reserved.