Endometrial autophagy is essential for embryo implantation during early pregnancy
Endometrial autophagy is essential for embryo implantation during early pregnancy
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子宫内膜自噬对于妊娠早期胚胎着床至关重要
DOI：
10.1007/s00109-019-01849-y
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通讯作者：
Ru-Fei Gao
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作者：
Yan Su;Juan-Juan Zhang;Jun-Lin He;Xue-Qing Liu;Xue-Mei Chen;Yu-Bin Ding;Chao Tong;Chuan Peng;Yan-Qing Geng;Ying-Xiong Wang;Ru-Fei Gao
胚胎着床是哺乳动物生殖过程中一个重要而复杂的过程。然而，几乎没有证据表明自噬参与了胚胎着床过程。为了确定自噬在妊娠小鼠围着床期子宫中的可能作用，我们首先检测了妊娠第4、5和6天(分别为D4、D5和D6)自噬相关标记物ATG5和LC3的表达。与D4相比，在胚胎附着于容受性子宫内膜后的D5和D6，自噬相关标记物的表达下调。进一步的检查显示，与植入部位相比，植入部位的自噬相关标记物ATG5、ATG12、LC3、组织蛋白酶B和p62显著降低。透射电子显微镜观察到植入部位的自噬小体数量较少。为了证实自噬在小鼠胚胎着床过程中的作用，我们给小鼠注射了自噬抑制剂3-甲基腺嘌呤和氯喹。经3-甲基腺嘌呤治疗后，蜕膜标志物HOXA10和孕激素受体的表达明显降低。此外，观察到氯喹处理后植入部位减少，HOXA10和PR蛋白水平增加。此外，在体内人工蜕膜化小鼠模型中，3-甲基腺嘌呤和氯喹抑制自噬后，观察到子宫蜕膜化受损和PR和HOXA10蛋白水平的失调。最后，在正常人的增生期、分泌期和蜕膜组织中也观察到了Lc3和p62的表达。综上所述，子宫内膜自噬可能是胚胎着床所必需的，它可能与早期妊娠的子宫内膜蜕膜化有关。关键信息·自噬相关标记物在着床部位显著减少。·自噬抑制导致异常蜕膜化。·自噬在胚胎着床中是必不可少的。
AbstractEmbryo implantation is an essential and complex process in mammalian reproduction. However, little evidence has indicated the involvement of autophagy during embryo implantation. To determine the possible role of autophagy in uterine of pregnant mice during the peri-implantation stage, we first examined the expression of autophagy-related markers ATG5 and LC3 on day 4, 5, and 6 of pregnancy (D4, D5, and D6, respectively). Compared with expression on D4, downregulation of the autophagy-related markers was observed on D5 and D6, the days after the embryo attached to the receptivity endometrium. Further examination showed that autophagy-related markers ATG5, ATG12, LC3, cathepsin B, and P62 at the implantation site were significantly decreased when comparing with the inter-implantation site. Fewer number of autophagosomes at the implantation site were also observed by transmission electron microscopy. To confirm the functional role of autophagy during embryo implantation in mice, we administered the autophagy inhibitor 3-methyladenine and chloroquine to mice. After treated with 3-methyladenine, the expression of decidual markers HOXA10 and progesterone receptor were significantly reduced. Furthermore, a reduction in implantation sites and increase in the HOXA10 and PR protein levels were observed in response to chloroquine treatment. In addition, impaired uterine decidualization and dysregulation of the PR and HOXA10 protein levels was observed after autophagy inhibited by 3-methyladenine and chloroquine in in vivo artificial decidualization mouse model. In the last, LC3 and P62 were also observed in normal human proliferative, secretory, and decidua tissues. In conclusion, endometrial autophagy may be essential for embryo implantation, and it may be associated with endometrial decidualization during early pregnancy.Key message• Autophagy-related markers were significantly decreased at implantation site.• Autophagy inhibition results in abnormal decidualization.• Autophagy is essential for embryo implantation.