Declined Expression of Histone Deacetylase 6 Contributes to Periodontal Ligament Stem Cell Aging
Declined Expression of Histone Deacetylase 6 Contributes to Periodontal Ligament Stem Cell Aging
复制标题
组蛋白脱乙酰酶 6 表达下降导致牙周膜干细胞老化。
DOI：
10.1902/jop.2016.160338
复制
发表时间：
2017-01-01
影响因子：
4.3
通讯作者：
Zhou, Yanheng
中科院分区：
文献类型：
--
作者：
Li, Qian;Ma, Yushi;Zhou, Yanheng
背景：识别衰老相关干细胞（SC）功能障碍的调节因子是干细胞生物学和基于干细胞的疗法中的一个关键课题。牙周膜干细胞（PDLSC）是一种具有牙齿再生潜力的牙间充质干细胞，在体内和体外扩增过程中都会随着年龄增长而出现功能退化。然而，对于PDLSC衰老的调节因子知之甚少。
方法：在各种模型中评估一种潜在的PDLSC衰老调节因子——组蛋白去乙酰化酶6（HDAC6）的表达变化。使用HDAC6特异性药物抑制剂或基于RNA干扰的基因敲低技术，检测HDAC6功能缺失模型中PDLSC衰老相关的表型和功能变化。通过p27（Kip1）的乙酰化和稳定性变化以及HDAC6的过表达或功能抑制，证明p27（Kip1）参与了与HDAC6相关的衰老过程。
结果：在复制性衰老和诱导性干细胞衰老模型中，HDAC6的表达显著降低。功能缺失实验表明，对HDAC6去乙酰化酶活性的药物抑制加速了PDLSC的衰老，并损害了其干细胞活性，表现为成骨分化能力降低和迁移能力减弱。对干细胞增殖耗竭标志物的检测显示，在HDAC6被抑制后，p27（Kip1）的蛋白水平特异性升高。HDAC6与p27（Kip1）发生物理相互作用，并能够使p27（Kip1）去乙酰化。重要的是，p27（Kip1）的乙酰化受HDAC6负调控，这与p27（Kip1）蛋白水平的变化相关。
结论：数据表明HDAC6在PDLSC衰老中起重要作用，这至少部分依赖于对p27（Kip1）乙酰化的调节。
Background: Identification of regulators for aging-associated stem cell (SC) dysfunctions is a critical topic in SC biology and SC-based therapies. Periodontal ligament stem cell (PDLSC), a kind of dental mesenchymal SC with dental regeneration potential, ages with functional deterioration in both in vivo and ex vivo expansion. However, little is known about regulators for PDLSC aging.Methods: Expression changes of a potential regulator for PDLSC aging, histone deacetylase 6 (HDAC6), were evaluated within various models. Senescence-associated phenotypic and functional alternations of PDLSC in loss-of-function models for HDAC6 were examined using HDAC6-specific pharmacologic inhibitors or RNA interference-based knockdown. Involvement of p27(Kip1) in HDAC6-associated aging was demonstrated by its acetylation and stability changes along with overexpression or functional inhibition of HDAC6.Results: Expression of HDAC6 decreased significantly in replicative senescence and induced SC aging models. Loss-of-function experiments suggested that pharmacologic inhibition of deacetylase activity of HDAC6 accelerated PDLSC senescence and impaired its SC activities, which showed reduced osteogenic differentiation and diminished migration capacities. Examination of markers for proliferative exhaustion of SCs revealed that protein level of p27(Kip1) was specifically elevated after HDAC6 inhibition. HDAC6 physically interacted with p27(Kip1) and could deacetylate p27(Kip1). Importantly, acetylation of p27(Kip1) was negatively regulated by HDAC6, which correlated with alteration of p27(Kip1) protein levels.Conclusion: Data suggest that HDAC6 plays an important role in PDLSC aging, which is dependent, at least partially, on regulation of p27(Kip1) acetylation.