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首页> 外文期刊>Aging cell. >Advanced Maternal Age-associated SIRT1 Deficiency Compromises Trophoblast Epithelial?Mesenchymal Transition through an Increase in Vimentin Acetylation
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Advanced Maternal Age-associated SIRT1 Deficiency Compromises Trophoblast Epithelial?Mesenchymal Transition through an Increase in Vimentin Acetylation

机译：先进的母体年龄相关的SIRT1缺乏损害滋养细胞上皮？间充质转换通过乙酰化的增加

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Advanced maternal age (AMA) pregnancies are rapidly increasing and are associated with aberrant trophoblast cell function, poor placentation, and unfavorable pregnancy outcomes, presumably due to premature placental senescence. SIRT1 is an NAD + -dependent deacetylase with well-known antiaging effects, but its connection with placental senescence is unreported. In this study, human term placentas and first-trimester villi were collected from AMA and normal pregnancies, and a mouse AMA model was established by cross breeding young and aged male and female C57 mice. SIRT1 expression and activity in HTR8/SVneo cells were genetically or pharmacologically manipulated. Trophoblast-specific Sirt1 -knockout (KO) mouse placentas were generated by mating Elf5 -Cre and Sirt1 fl/fl mice. Trophoblast cell mobility was assessed with transwell invasion and wound-healing assays. SIRT1-binding proteins in HTR8/SVneo cells and human placental tissue were identified by mass spectrometry. We identified SIRT1 as the only differentially expressed sirtuin between AMA and normal placentas. It is downregulated in AMA placentas early in the placental life cycle and is barely impacted by paternal age. SIRT1 loss upregulates P53 acetylation and P21 expression and impairs trophoblast invasion and migration. Sirt1 -KO mouse placentas exhibit senescence markers and morphological disruption, along with decreased fetal weight. In trophoblasts, SIRT1 interacts with vimentin, regulating its acetylation. In conclusion, SIRT1 promotes trophoblast epithelial?mesenchymal transition (EMT) to enhance invasiveness by modulating vimentin acetylation. AMA placentas are associated with premature senescence during placentation due to SIRT1 loss. Therefore, SIRT1 may be an antiaging therapeutic target for improving placental development and perinatal outcomes in AMA pregnancies.
机译：先进的产妇年龄（AMA）怀孕正在迅速增加，并且与异常滋养细胞功能，沉重亢进和不利的妊娠结果有关，可能是由于过早的胎盘衰老。 SIRT1是一种NAD + - 依赖性脱乙酰化酶，具有众所周知的抗衰效效应，但与胎盘衰老的连接是未报告的。在这项研究中，从AMA和正常怀孕中收集了人类术语胎盘和初三孕期绒毛，并通过交叉育种年轻和老年男性C57小鼠建立了小鼠AMA模型。 HTR8 / Svneo细胞中的SIRT1表达和活性在遗传上或药理学上进行制衡。通过配合ELF5 -CRE和SIRT1 FL / FL小鼠产生滋养细胞特异性SIRT1-KNOCKOUT（KO）小鼠胎盘。用Transwell侵袭和伤口愈合测定评估滋养细胞迁移率。通过质谱法鉴定HTR8 / SVNEO细胞中的SIRT1结合蛋白和人的胎盘组织。我们识别SIRT1，因为唯一表达了AMA和正常胎盘之间的SIRTUIN。它在胎盘生命周期早期在AMA胎盘下调，几乎受到父亲年龄的影响。 SIRT1损失上调P53乙酰化和P21表达，损害滋养流侵入和迁移。 SIRT1 -KO小鼠胎盘表现出衰老标记和形态破坏，胎儿重量降低。在滋养细胞中，SIRT1与Vimentin相互作用，调节其乙酰化。总之，SIRT1促进滋养细胞上皮？间充质转换（EMT）以通过调节乙酰化来增强侵袭性。由于SIRT1损失，AMA胎盘在置入期间与过早衰老有关。因此，SIRT1可以是改善AMA妊娠中的胎盘发育和围产期结果的抗衰率治疗靶标。

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