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Review
. 2019 May 24;18(3):234-240.
doi: 10.1002/rmb2.12280. eCollection 2019 Jul.

Uterine receptivity, embryo attachment, and embryo invasion: Multistep processes in embryo implantation

Yamato Fukui  1 , Yasushi Hirota  1 , Mitsunori Matsuo  1 , Mona Gebril  1 , Shun Akaeda  1 , Takehiro Hiraoka  1 , Yutaka Osuga  1
Affiliations
Review

Uterine receptivity, embryo attachment, and embryo invasion: Multistep processes in embryo implantation

Yamato Fukui et al. Reprod Med Biol. .

Abstract

Background: Recurrent implantation failure is a critical issue in IVF-ET treatment. Successful embryo implantation needs appropriate molecular and cellular communications between embryo and uterus. Rodent models have been used intensively to understand these mechanisms.

Methods: The molecular and cellular mechanisms of embryo implantation were described by referring to the previous literature investigated by us and others. The studies using mouse models of embryo implantation were mainly cited.

Results: Progesterone (P4) produced by ovarian corpus luteum provides the uterus with receptivity to the embryo, and uterine epithelial growth arrest and stromal proliferation, what we call uterine proliferation-differentiation switching (PDS), take place in the peri-implantation period before embryo attachment. Uterine PDS is a hallmark of uterine receptivity, and several genes such as HAND2 and BMI1, control uterine PDS by modulating P4-PR signaling. As the next implantation process, embryo attachment onto the luminal epithelium occurs. This process is regulated by FOXA2-LIF pathway and planar cell polarity signaling. Then, the luminal epithelium at the embryo attachment site detaches from the stroma, which enables trophoblast invasion. This process of embryo invasion is regulated by HIF2α in the stroma.

Conclusion: These findings indicate that embryo implantation contains multistep processes regulated by specific molecular pathways.

Keywords: cell proliferation; embryo implantation; infertility; mouse models; uterine receptivity.

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Conflict of interest statement

Conflict of interest: The authors declare that they have no conflict of interest. Human/animal rights: This article does not contain any studies with human and animal subjects performed by the any of the authors.

Figures

Figure 1
Figure 1
Molecular pathways involved in uterine proliferation‐differentiation switching (PDS). Progesterone, P4; progesterone receptor, PR; 52‐kDa FK506 binding protein, FKBP52; microRNA‐200a, miR‐200a; Indian hedgehog, IHH; Van Gogh‐like 2, VANGL2; patched‐1, PTCH1; COUP transcription factor 2, COUP‐TFII; B lymphoma Mo‐MLV insertion region 1 homolog, BMI1; nuclear receptor co‐activator 6, NCOA6; SRC homology 2 domain‐containing protein tyrosine phosphatase‐2, SHP2; estrogen receptor α, ERα; early growth response protein 1, EGR1; heart and neural crest derivatives‐expressed protein 2, HAND2
Figure 2
Figure 2
Key signals and pathways in the multistep processes of embryo implantation. Progesterone, P4; progesterone receptor, PR; proliferation‐differentiation switching, PDS; planar cell polarity, PCP; forkhead box protein A2, FOXA2; leukemia inhibitory factor, LIF; signal transducer and activator of transcription 3, STAT3; hypoxia‐inducible factor 2α, HIF2α
Figure 3
Figure 3
Stromal HIF2α regulates embryo invasion
See this image and copyright information in PMC

References

    1. Ombelet W, Cooke I, Dyer S, Serour G, Devroey P. Infertility and the provision of infertility medical services in developing countries. Hum Reprod Update. 2008;14(6):605‐621. - PMC - PubMed
    1. Nachtigall RD. International disparities in access to infertility services. Fertil Steril. 2006;85(4):871‐875. - PubMed
    1. Mascarenhas MN, Flaxman SR, Boerma T, Vanderpoel S, Stevens GA. National, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys. PLoS Med. 2012;9(12):e1001356. - PMC - PubMed
    1. Vander Borght M, Wyns C. Fertility and infertility: definition and epidemiology. Clin Biochem. 2018;62:2‐10. - PubMed
    1. Dey SK, Lim H, Das SK, et al. Molecular cues to implantation. Endocr Rev. 2004;25(3):341‐373. - PubMed