Overexpressed Sirt1 in MSCs Promotes Dentin Formation in Bmi1-Deficient Mice
Overexpressed Sirt1 in MSCs Promotes Dentin Formation in Bmi1-Deficient Mice
复制标题
MSC 中过度表达 Sirt1 可促进 Bmi1 缺陷小鼠的牙本质形成。
DOI：
10.1177/0022034518781509
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发表时间：
2018-11-01
影响因子：
7.6
通讯作者：
Sun, W.
中科院分区：
文献类型：
--
作者：
Wang, H.;Lv, C.;Sun, W.
Sirt 1促进人牙髓细胞中成牙本质细胞基因的表达，而抑制Sirt 1则下调这些基因的表达。为探讨Prx 1启动子驱动的Sirt 1基因过表达对Bmi 1基因敲除小鼠牙本质形成的影响，建立了Sirt 1基因过表达的Bmi 1（TG）小鼠骨髓间充质干细胞（MSCs）模型。首先，我们使用Prx 1-Cre/ROSA（nTnG）小鼠证明，Prx 1谱系细胞主要存在于4周龄的髓角。第二，我们发现4周龄的Sirt 1（TG）小鼠与野生型（WT）同窝小鼠相比，牙齿体积增加。Sirt 1（TG）小鼠牙乳头间充质细胞中Sirt 1的表达水平显著高于WT小鼠。此外，我们证明，牙齿矿化，牙齿体积，牙本质唾液蛋白免疫阳性区域，成牙本质细胞基因表达，和增殖BrdU阳性细胞的百分比显着升高Sirt 1（TG）小鼠和显着降低Bmi 1（-/-）小鼠与WT同窝出生4周龄。然而，与WT同窝小鼠相比，Sirt 1（TG）小鼠的前牙本质面积和TUNEL阳性凋亡细胞百分比显著减少，但Bmi 1（-/-）小鼠的前牙本质面积和TUNEL阳性凋亡细胞百分比显著增加。所有这些参数在Sirt 1（TG）Bmi 1（-/-）小鼠与Bmi 1（-/-）小鼠中得到挽救。最后，通过使用牙乳头间充质细胞，我们发现Sirt 1的过表达挽救了由Bmi 1缺陷引起的细胞增殖和分化的降低，并增加了细胞凋亡，这与p53脱乙酰化的增加有关。因此，这项研究表明，Sirt 1是一个潜在的治疗目标，促进牙本质形成的合成代谢的方法来治疗牙齿发育缺陷。
Sirt1 promotes odontoblastic gene expression in human dental pulp cells, whereas the inhibition of Sirt1 downregulates the expression of those genes. To investigate whether the overexpression of Sirt1 in mesenchymal stem cells (MSCs) driven by Prx1 promoter could rescue the dentin formation defects in Bmi1-deficient (Bmi1(-/-)) mice, we established the MSCs overexpressing Sirt1 in Bmi1 knockout mice (Sirt1(TG)Bmi1(-/-)). First, we used Prx1-Cre/ROSA(nTnG) mice to demonstrate that Prx1 linage cells exist mainly in the pulp horns at 4 wk of age. Second, we found that 4-wk-old Sirt1(TG) mice had increased tooth volume as compared with wild-type (WT) littermates. The expression level of Sirt1 was significantly higher in dental papilla mesenchymal cells of Sirt1(TG) mice than WT mice. Furthermore, we demonstrated that the tooth mineralization, dental volume, dentin sialoprotein-immunopositive areas, odontoblastic gene expression, and percentage of proliferating BrdU-positive cells were significantly elevated in the Sirt1(TG) mice and dramatically reduced in the Bmi1(-/-) mice versus the WT littermates at 4 wk of age. However, the areas of predentin and the percentage of TUNEL-positive apoptotic cells were significantly reduced in the Sirt1(TG) mice but dramatically increased in the Bmi1(-/-) mice as compared with the WT littermates. All these parameters were rescued in the Sirt1(TG)Bmi1(-/-) mice versus the Bmi1(-/-) mice. Finally, by using dental papilla mesenchymal cells, we found that the overexpression of Sirt1 rescued the reduced cell proliferation and differentiation and increased the cell apoptosis caused by Bmi1 deficiency, which was associated with increased p53 deacetylation. Therefore, this study indicates that Sirt1 is a potential therapeutic target for promoting dentin formation in an anabolic approach to the treatment of dental developmental defects.