PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, PO Box 5000, 90014, Oulu, Finland.
Department of Children and Adolescents, Oulu University Hospital, 90014, Oulu, Finland.
BMC Med. 2022 Apr 28;20(1):141. doi: 10.1186/s12916-022-02339-8.
Preterm birth is defined as live birth before 37 completed weeks of pregnancy, and it is a major problem worldwide. The molecular mechanisms that lead to onset of spontaneous preterm birth are incompletely understood. Prediction and evaluation of the risk of preterm birth is challenging as there is a lack of accurate biomarkers. In this study, our aim was to identify placental proteins that associate with spontaneous preterm birth.
We analyzed the proteomes from placentas to identify proteins that associate with both gestational age and spontaneous labor. Next, rare and potentially damaging gene variants of the identified protein candidates were sought for from our whole exome sequencing data. Further experiments we performed on placental samples and placenta-associated cells to explore the location and function of the spontaneous preterm labor-associated proteins in placentas.
Exome sequencing data revealed rare damaging variants in SERPINA1 in families with recurrent spontaneous preterm deliveries. Protein and mRNA levels of alpha-1 antitrypsin/SERPINA1 from the maternal side of the placenta were downregulated in spontaneous preterm births. Alpha-1 antitrypsin was expressed by villous trophoblasts in the placenta, and immunoelectron microscopy showed localization in decidual fibrinoid deposits in association with specific extracellular proteins. siRNA knockdown in trophoblast-derived HTR8/SVneo cells revealed that SERPINA1 had a marked effect on regulation of the actin cytoskeleton pathway, Slit-Robo signaling, and extracellular matrix organization.
Alpha-1 antitrypsin is a protease inhibitor. We propose that loss of the protease inhibition effects of alpha-1 antitrypsin renders structures critical to maintaining pregnancy susceptible to proteases and inflammatory activation. This may lead to spontaneous premature birth.
早产是指妊娠满 37 周前的分娩，这是一个全球性的主要问题。导致自发性早产的分子机制尚未完全了解。由于缺乏准确的生物标志物，早产的预测和评估具有挑战性。在这项研究中，我们的目的是确定与自发性早产相关的胎盘蛋白。
我们分析了胎盘的蛋白质组，以鉴定与胎龄和自发性分娩相关的蛋白质。接下来，我们从全外显子测序数据中寻找鉴定出的蛋白候选物的罕见和潜在有害的基因变异。我们还对胎盘样本和胎盘相关细胞进行了进一步的实验，以探索与自发性早产相关的蛋白在胎盘中的位置和功能。
外显子组测序数据显示，在复发性自发性早产的家庭中，SERPINA1 存在罕见的有害变异。自发性早产中胎盘母体侧的α-1 抗胰蛋白酶/SERPINA1 蛋白和 mRNA 水平下调。α-1 抗胰蛋白酶在胎盘的绒毛滋养细胞中表达，免疫电子显微镜显示其在与特定细胞外蛋白结合的蜕膜纤维蛋白沉积物中的定位。在滋养细胞衍生的 HTR8/SVneo 细胞中进行 siRNA 敲低显示，SERPINA1 对肌动蛋白细胞骨架途径、Slit-Robo 信号和细胞外基质组织的调节有显著影响。
α-1 抗胰蛋白酶是一种蛋白酶抑制剂。我们提出，α-1 抗胰蛋白酶的蛋白酶抑制作用丧失使维持妊娠的结构易受蛋白酶和炎症激活的影响。这可能导致自发性早产。
