Amnion-Derived Mesenchymal Stem Cell Exosomes-Mediated Autophagy Promotes the Survival of Trophoblasts Under Hypoxia Through mTOR Pathway by the Downregulation of EZH2.
Amnion-Derived Mesenchymal Stem Cell Exosomes-Mediated Autophagy Promotes the Survival of Trophoblasts Under Hypoxia Through mTOR Pathway by the Downregulation of EZH2.
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DOI：
10.3389/fcell.2020.545852
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发表时间：
2020
影响因子：
5.5
通讯作者：
Ye Y
中科院分区：
文献类型：
--
作者：
Chu Y;Chen W;Peng W;Liu Y;Xu L;Zuo J;Zhou J;Zhang Y;Zhang N;Li J;Liu L;Yao K;Gao G;Wang X;Han R;Liu C;Li Y;Zhou H;Huang Y;Ye Y
人骨髓间充质干细胞（AD-MSCs）已被报道为一种有希望的有效治疗组织修复的方法。妊娠期滋养细胞功能障碍与子痫前期的发病密切相关。为了了解AD-MSC如何调节滋养层功能，我们在缺氧条件下用AD-MSC衍生的外泌体处理滋养层。处理显著增强滋养细胞增殖和自噬。此外，在AD-MSC外泌体处理的滋养层细胞中观察到EZH 2水平的显著降低和mTOR信号转导的失活。与这些发现一致，EZH 2的过表达激活了滋养层中的mTOR信号传导，并减少了滋养层的自噬和存活，即使在存在AD-MSC衍生的外泌体的情况下。此外，EZH 2抑制表现出与AD-MSC衍生的外泌体诱导的相同的滋养层自噬促进作用，也伴随着mTOR信号转导的失活。重要的是，当EZH 2在用特异性mTOR信号传导抑制剂PQR 620处理的滋养层中过表达时，滋养层中的自噬和增殖减少。对人胎盘外植体的研究也证实了我们的发现，显示EZH 2和mTOR的表达水平降低，而自噬相关蛋白水平通过AD-MSC衍生的外泌体处理增加。总之，我们的研究结果表明，由AD-MSC衍生的外泌体介导的EZH 2依赖性mTOR信号转导失活是缺氧滋养细胞自噬增强的先决条件。
Human amnion-derived mesenchymal stem cells (AD-MSCs) have been reported as a promising effective treatment to repair tissue. Trophoblast dysfunction during pregnancy is significantly involved in the pathogenesis of preeclampsia (PE). To understand how AD-MSCs regulated trophoblast function, we treated trophoblasts with AD-MSC-derived exosomes under hypoxic conditions. The treatment markedly enhanced the trophoblast proliferation and autophagy. Furthermore, significant decrease of EZH2 levels and inactivation of mTOR signaling were observed in AD-MSC exosomes-treated trophoblasts. Consistent with these findings, overexpression of EZH2 activated the mTOR signaling in trophoblasts, and reduced the autophagy and survival of trophoblasts, even in the presence of AD-MSC-derived exosomes. In addition, EZH2 inhibition exhibited the same trophoblast autophagy-promoting effect as induced by AD-MSC-derived exosomes, also accompanied by the inactivation of mTOR signaling. Importantly, when EZH2 was overexpressed in trophoblasts treated with PQR620, a specific mTOR signaling inhibitor, the autophagy and proliferation in trophoblasts were decreased. Studies on human placental explants also confirmed our findings by showing that the expression levels of EZH2 and mTOR were decreased while the autophagy-associated protein level was increased by AD-MSC-derived exosome treatment. In summary, our results suggest that EZH2-dependent mTOR signaling inactivation mediated by AD-MSC-derived exosomes is a prerequisite for autophagy augmentation in hypoxic trophoblasts.