Hypoxia-Reoxygenation Impairs Autophagy-Lysosomal Machinery in Primary Human Trophoblasts Mimicking Placental Pathology of Early-Onset Preeclampsia.
Hypoxia-Reoxygenation Impairs Autophagy-Lysosomal Machinery in Primary Human Trophoblasts Mimicking Placental Pathology of Early-Onset Preeclampsia.
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DOI：
10.3390/ijms23105644
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发表时间：
2022-05-18
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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我们以前已经描述过，胎盘自噬的激活是正常妊娠的一个主要特征，而自噬在先兆子痫(PE)中是受损的。在这里，我们展示了缺氧-复氧(H/R)治疗对维持原代人滋养层细胞(PHTs)自噬-溶酶体通量的关键分子的失调。用透射电子显微镜进行的超微结构分析显示，在H/R暴露的PHTs中，自噬小体和自溶酶体显著减少。H/R诱导的蛋白质聚集物的积累遵循与溶酶体干扰物氯喹处理的PHTs类似的模式。重要的是，早发性PE分娩的胎盘表现出与H/R治疗的PHTs相同的特征。综上所述，我们的结果表明，H/R扰乱了PHTs的自噬机制，早发性PE所致的胎盘自噬受损类似于H/R治疗的PHTs。值得注意的是，评估自噬过程每个阶段的关键调控因子，特别是溶酶体的完整性，以及验证自噬超微结构，对于准确评估来自PE分娩的人滋养细胞和胎盘组织的自噬活性是至关重要的。
We have previously described that placental activation of autophagy is a central feature of normal pregnancy, whereas autophagy is impaired in preeclampsia (PE). Here, we show that hypoxia–reoxygenation (H/R) treatment dysregulates key molecules that maintain autophagy–lysosomal flux in primary human trophoblasts (PHTs). Ultrastructural analysis using transmission electron microscopy reveals a significant reduction in autophagosomes and autolysosomes in H/R-exposed PHTs. H/R-induced accumulation of protein aggregates follows a similar pattern that occurs in PHTs treated with a lysosomal disruptor, chloroquine. Importantly, the placenta from early-onset PE deliveries exhibits the same features as seen in H/R-treated PHTs. Taken together, our results indicate that H/R disrupts autophagic machinery in PHTs and that impaired autophagy in the placenta from early-onset PE deliveries mimics the events in H/R-treated PHTs. Notably, assessment of key regulators at each stage of autophagic processes, especially lysosomal integrity, and verification of autophagic ultrastructure are essential for an accurate evaluation of autophagy activity in human trophoblasts and placental tissue from PE deliveries.
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