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Endometrial autophagy is essential for embryo implantation during early pregnancy

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Abstract

Embryo 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.

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Funding

This work was supported by the National Natural Science Foundation of China (Nos. 31771663, 31571190, and 81300486) and the Natural Science Foundation of Chongqing (No. cstc2018jcyjAX0309).

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Authors and Affiliations

  1. Laboratory of Reproductive Biology, School of Public Health, Chongqing Medical University, Chongqing, 400016, China

    Yan Su, Juan-Juan Zhang, Jun-Lin He, Xue-Qing Liu, Xue-Mei Chen, Yu-Bin Ding, Yan-Qing Geng, Ying-Xiong Wang & Ru-Fei Gao

  2. Joint International Research Laboratory of Reproduction&Development, Chongqing, 400016, China

    Yan Su, 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

  3. Reproductive Medicine Centre, Taihe Hospital, Hubei University of Medicine, 32 South Renmin Road, Shiyan, 442000, Hubei, China

    Juan-Juan Zhang

  4. Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Chao Tong

  5. The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Chuan Peng

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  1. Yan Su
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Correspondence to Ying-Xiong Wang or Ru-Fei Gao.

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Su, Y., Zhang, JJ., He, JL. et al. Endometrial autophagy is essential for embryo implantation during early pregnancy. J Mol Med 98, 555–567 (2020). https://doi.org/10.1007/s00109-019-01849-y

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