HDAC Inhibitor Trichostatin A Promotes Proliferation and Odontoblast Differentiation of Human Dental Pulp Stem Cells
HDAC Inhibitor Trichostatin A Promotes Proliferation and Odontoblast Differentiation of Human Dental Pulp Stem Cells
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DOI：
10.1089/ten.tea.2012.0163
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发表时间：
2013-03-01
影响因子：
4.1
通讯作者：
Choung, Pill-Hoon
中科院分区：
文献类型：
--
作者：
Jin, Hexiu;Park, Joo-Young;Choung, Pill-Hoon
Trichostatin A （TSA）是一种有效的组蛋白去乙酰化酶（HDAC）抑制剂，具有广谱的表观遗传活性，已知可调节多种细胞机制，包括间充质干细胞的分化。在这项研究中，我们证明了TSA在体外促进人牙髓干细胞（hDPSCs）的增殖和成牙质分化，并在体内促进牙本质的形成和成牙质分化。我们观察到TSA在一定浓度下增加了hDPSC增殖细胞核抗原和cyclin D1的表达，JNK/c-Jun通路的激活是TSA依赖性hDPSC增殖的必要条件。此外，TSA加速了体外矿物结节的形成，增加了牙本质唾液磷酸蛋白、牙本质基质蛋白1、骨唾液蛋白和骨钙素的基因表达。此外，TSA显著上调磷酸化smad2 /3、Smad4和核因子I-C的水平，而Smad3的特异性抑制剂抑制TSA，增强hdpsc的矿化分化。HDAC3被TSA治疗下调，提示HDAC家族成员中TSA依赖通路的可能中介。此外，tsa注射胚胎的牙本质厚度增加，牙本质面积增大，出生后磨牙成牙细胞数量增加，免疫组织化学染色显示牙本质唾液蛋白表达增强。这些结果表明，TSA可能在牙发育阶段hdpsc的增殖和成牙细胞分化中起关键作用，并可作为牙硬组织工程的促进剂。
Trichostatin A (TSA) is a potent histone deacetylase (HDAC) inhibitor with a broad spectrum of epigenetic activities known to regulate diverse cellular mechanisms, including differentiation of mesenchymal stem cells. In this study, we demonstrate that TSA promotes proliferation and odontoblast differentiation of human dental pulp stem cells (hDPSCs) in vitro and has the ability to enhance dentin formation and odontoblast differentiation in vivo during tooth development. We observed that TSA increased the expression of proliferating cell nuclear antigen and cyclin D1 in hDPSCs at a certain concentration and the activation of JNK/c-Jun pathway was essential for TSA-dependent hDPSC proliferation. Further, TSA accelerated mineral nodule formation in vitro and increased gene expression of dentin sialophosphoprotein, dentin matrix protein 1, bone sialoprotein, and osteocalcin. In addition, TSA significantly upregulated the levels of phospho-Smad2/3, Smad4, and nuclear factor I-C, while the specific inhibitor of Smad3 inhibits TSA enhancing mineralization differentiation of hDPSCs. HDAC3 is downregulated by TSA treatment, suggesting a possible mediator of TSA-dependent pathways among the members of HDAC family. Moreover, TSA-injected embryos exhibited increased dentin thickness, larger dentin areas, and higher odontoblast numbers in their postnatal molars with stronger dentin sialoprotein expression in immunohistochemical staining. These findings indicate that TSA may serve a key role in proliferation and odontoblast differentiation of hDPSCs in dental developmental stages and can be used as an accelerator in dental hard tissue engineering.