DNA Demethylation Rescues the Impaired Osteogenic Differentiation Ability of Human Periodontal Ligament Stem Cells in High Glucose.
DNA Demethylation Rescues the Impaired Osteogenic Differentiation Ability of Human Periodontal Ligament Stem Cells in High Glucose.
复制标题
DNA 去甲基化可挽救高血糖条件下受损的人牙周膜干细胞成骨分化能力
DOI：
10.1038/srep27447
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发表时间：
2016-06-08
影响因子：
4.6
通讯作者：
Tian W
中科院分区：
文献类型：
--
作者：
Liu Z;Chen T;Sun W;Yuan Z;Yu M;Chen G;Guo W;Xiao J;Tian W
糖尿病的特征是血糖水平异常高，会导致骨骼重塑受损。人牙周膜干细胞(HPDLSCs)在高糖(HG)刺激下成骨分化能力减弱，与牙槽骨丢失有关。最近，DNA甲基化被报道在病理状态下影响干细胞的成骨分化。然而，DNA甲基化与HG诱导的成骨分化能力之间的内在联系仍不清楚。在本研究中，我们发现随着牙周韧带DNA甲基化水平的升高，糖尿病大鼠表现出骨量和密度的降低。在体外应用DNA甲基转移酶抑制剂5-氮杂-2‘-脱氧胞苷(5-aza-2’-deoxcytidine，5-aza-2‘-deoxcytidine，5-aza-2’-deoxcytidine)降低hPDLSCs的DNA甲基化水平，挽救hPDLSCs在HG条件下的成骨分化能力。此外，我们还证明了在此过程中典型的Wnt信号通路被激活，并且在HG环境下，5-aza-DC拯救的成骨分化能力被典型Wnt信号通路的有效拮抗剂Dickkopf-1阻断。综上所述，这些结果首次证明，抑制DNA甲基化能够通过激活规范的Wnt信号通路促进HG暴露的hPDLSCs的成骨分化能力。
Diabetes mellitus, characterized by abnormally high blood glucose levels, gives rise to impaired bone remodeling. In response to high glucose (HG), the attenuated osteogenic differentiation capacity of human periodontal ligament stem cells (hPDLSCs) is associated with the loss of alveolar bone. Recently, DNA methylation was reported to affect osteogenic differentiation of stem cells in pathological states. However, the intrinsic mechanism linking DNA methylation to osteogenic differentiation ability in the presence of HG is still unclear. In this study, we found that diabetic rats with increased DNA methylation levels in periodontal ligaments exhibited reduced bone mass and density.In vitroapplication of 5-aza-2′-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, to decrease DNA methylation levels in hPDLSCs, rescued the osteogenic differentiation capacity of hPDLSCs under HG conditions. Moreover, we demonstrated that the canonical Wnt signaling pathway was activated during this process and, under HG circumstances, the 5-aza-dC-rescued osteogenic differentiation capacity was blocked by Dickkopf-1, an effective antagonist of the canonical Wnt signaling pathway. Taken together, these results demonstrate for the first time that suppression of DNA methylation is able to facilitate the osteogenic differentiation capacity of hPDLSCs exposed to HG, through activation of the canonical Wnt signaling pathway.