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

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

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.

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

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.
    1. Nachtigall RD. International disparities in access to infertility services. Fertil Steril. 2006;85(4):871‐875.
    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.
    1. Vander Borght M, Wyns C. Fertility and infertility: definition and epidemiology. Clin Biochem. 2018;62:2‐10.
    1. Dey SK, Lim H, Das SK, et al. Molecular cues to implantation. Endocr Rev. 2004;25(3):341‐373.
    1. Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006;7(3):185‐199.
    1. Cha J, Sun X, Dey SK. Mechanisms of implantation: strategies for successful pregnancy. Nat Med. 2012;18(12):1754‐1767.
    1. Egashira M, Hirota Y. Uterine receptivity and embryo‐uterine interactions in embryo implantation: lessons from mice. Reprod Med Biol. 2013;12(4):127‐132.
    1. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345(19):1400‐1408.
    1. Lydon JP, DeMayo FJ, Funk CR, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995;9(18):2266‐2278.
    1. Mulac‐Jericevic B, Mullinax RA, DeMayo FJ, Lydon JP, Conneely OM. Subgroup of reproductive functions of progesterone mediated by progesterone receptor‐B isoform. Science. 2000;289(5485):1751‐1754.
    1. Tranguch S, Wang H, Daikoku T, Xie H, Smith DF, Dey SK. FKBP52 deficiency‐conferred uterine progesterone resistance is genetic background and pregnancy stage specific. J Clin Invest. 2007;117(7):1824‐1834.
    1. Carson DD, Bagchi I, Dey SK, et al. Embryo implantation. Dev Biol. 2000;223(2):217‐237.
    1. Haraguchi H, Saito‐Fujita T, Hirota Y, et al. MicroRNA‐200a locally attenuates progesterone signaling in the cervix, preventing embryo implantation. Mol Endocrinol. 2014;28(7):1108‐1117.
    1. Matsumoto L, Hirota Y, Saito‐Fujita T, et al. HIF2α in the uterine stroma permits embryo invasion and luminal epithelium detachment. J Clin Invest. 2018;128(7):3186‐3197.
    1. Urman B, Yakin K, Balaban B. Recurrent implantation failure in assisted reproduction: how to counsel and manage. A. General considerations and treatment options that may benefit the couple. Reprod Biomed Online. 2005;11(3):371‐381.
    1. van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2011;10:CD009154.
    1. Hirota Y, Cha J, Dey SK. Revisiting reproduction: prematurity and the puzzle of progesterone resistance. Nat Med. 2010;16(5):529‐531.
    1. Tranguch S, Smith DF, Dey SK. Progesterone receptor requires a co‐chaperone for signalling in uterine biology and implantation. Reprod Biomed Online. 2006;13(5):651‐660.
    1. Tranguch S, Cheung‐Flynn J, Daikoku T, et al. Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation. Proc Natl Acad Sci USA. 2005;102(40):14326‐14331.
    1. Dugan LL, Kim JS, Zhang Y, et al. Differential effects of cAMP in neurons and astrocytes. Role of B‐raf. J Biol Chem. 1999;274(36):25842‐25848.
    1. García AJ, Vega MD, Boettiger D. Modulation of cell proliferation and differentiation through substrate‐dependent changes in fibronectin conformation. Mol Biol Cell. 1999;10(3):785‐798.
    1. Conti L, Sipione S, Magrassi L, et al. Shc signaling in differentiating neural progenitor cells. Nat Neurosci. 2001;4(6):579‐586.
    1. Chen J‐F, Mandel EM, Thomson JM, et al. The role of microRNA‐1 and microRNA‐133 in skeletal muscle proliferation and differentiation. Nat Genet. 2006;38(2):228‐233.
    1. Daikoku T, Cha J, Sun X, et al. Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity. Dev Cell. 2011;21(6):1014‐1025.
    1. Li Q, Kannan A, DeMayo FJ, et al. The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science. 2011;331(6019):912‐916.
    1. Kawagoe J, Li Q, Mussi P, et al. Nuclear receptor coactivator‐6 attenuates uterine estrogen sensitivity to permit embryo implantation. Dev Cell. 2012;23(4):858‐865.
    1. Ran H, Kong S, Zhang S, et al. Nuclear Shp2 directs normal embryo implantation via facilitating the ERα tyrosine phosphorylation by the Src kinase. Proc Natl Acad Sci USA. 2017;114(18):4816‐4821.
    1. Xin Q, Kong S, Yan J, et al. Polycomb subunit BMI1 determines uterine progesterone responsiveness essential for normal embryo implantation. J Clin Invest. 2018;128(1):175‐189.
    1. Mulac‐Jericevic B, Lydon JP, DeMayo FJ, Conneely OM. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform. Proc Natl Acad Sci USA. 2003;100(17):9744‐9749.
    1. Ma WG, Song H, Das SK, Paria BC, Dey SK. Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Proc Natl Acad Sci USA. 2003;100(5):2963‐2968.
    1. Diana M, Schettini M, Gallucci M. Evaluation and management of malfunctionings following implantation of the artificial urinary sphincter. Int Surg. 1999;84(3):241‐245.
    1. Apparao KB, Lovely LP, Gui Y, Lininger RA, Lessey BA. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome. Biol Reprod. 2002;66(2):297‐304.
    1. Gregory CW, Wilson EM, Apparao K, et al. Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium. J Clin Endocrinol Metab. 2002;87(6):2960‐2966.
    1. Khorram O, Lessey BA. Alterations in expression of endometrial endothelial nitric oxide synthase and alpha(v)beta(3) integrin in women with endometriosis. Fertil Steril. 2002;78(4):860‐864.
    1. Mukherjee A, Amato P, Craig‐Allred D, DeMayo FJ, O'Malley BW, Lydon JP. Steroid receptor coactivator 2: an essential coregulator of progestin‐induced uterine and mammary morphogenesis. Ernst Schering Found Symp Proc. 2007;1:55‐76.
    1. Mahajan MA, Samuels HH. A new family of nuclear receptor coregulators that integrate nuclear receptor signaling through CREB‐binding protein. Mol Cell Biol. 2000;20(14):5048‐5063.
    1. Lee SK, Anzick SL, Choi JE, et al. A nuclear factor, ASC‐2, as a cancer‐amplified transcriptional coactivator essential for ligand‐dependent transactivation by nuclear receptors in vivo. J Biol Chem. 1999;274(48):34283‐34293.
    1. Ko L, Cardona GR, Chin WW. Thyroid hormone receptor‐binding protein, an LXXLL motif‐containing protein, functions as a general coactivator. Proc Natl Acad Sci USA. 2000;97(11):6212‐6217.
    1. Caira F, Antonson P, Pelto‐Huikko M, Treuter E, Gustafsson JA. Cloning and characterization of RAP250, a novel nuclear receptor coactivator. J Biol Chem. 2000;275(8):5308‐5317.
    1. Cheng JG, Chen JR, Hernandez L, Alvord WG, Stewart CL. Dual control of LIF expression and LIF receptor function regulate Stat3 activation at the onset of uterine receptivity and embryo implantation. Proc Natl Acad Sci USA. 2001;98(15):8680‐8685.
    1. Sun X, Bartos A, Whitsett JA, Dey SK. Uterine deletion of Gp130 or Stat3 shows implantation failure with increased estrogenic responses. Mol Endocrinol. 2013;27(9):1492‐1501.
    1. Matsumoto H, Zhao X, Das SK, Hogan BL, Dey SK. Indian hedgehog as a progesterone‐responsive factor mediating epithelial‐mesenchymal interactions in the mouse uterus. Dev Biol. 2002;245(2):280‐290.
    1. Lee K, Jeong JaeWook, Kwak I, et al. Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat Genet. 2006;38(10):1204‐1209.
    1. Wei Q, Levens ED, Stefansson L, Nieman LK. Indian Hedgehog and its targets in human endometrium: menstrual cycle expression and response to CDB‐2914. J Clin Endocrinol Metab. 2010;95(12):5330‐5337.
    1. Kurihara I, Lee D‐K, Petit FG, et al. COUP‐TFII mediates progesterone regulation of uterine implantation by controlling ER activity. PLoS Genet. 2007;3(6):e102.
    1. Kim H‐R, Kim YS, Yoon JA, et al. Estrogen induces EGR1 to fine‐tune its actions on uterine epithelium by controlling PR signaling for successful embryo implantation. FASEB J. 2018;32(3):1184‐1195.
    1. Swirnoff AH, Milbrandt J. DNA‐binding specificity of NGFI‐A and related zinc finger transcription factors. Mol Cell Biol. 1995;15(4):2275‐2287.
    1. Bhattacharyya S, Fang F, Tourtellotte W, Varga J. Egr‐1: new conductor for the tissue repair orchestra directs harmony (regeneration) or cacophony (fibrosis). J Pathol. 2013;229(2):286‐297.
    1. Kim H‐R, Kim YS, Yoon JA, et al. Egr1 is rapidly and transiently induced by estrogen and bisphenol A via activation of nuclear estrogen receptor‐dependent ERK1/2 pathway in the uterus. Reprod Toxicol. 2014;50:60‐67.
    1. Liang X‐H, Deng W‐B, Li M, et al. Egr1 protein acts downstream of estrogen‐leukemia inhibitory factor (LIF)‐STAT3 pathway and plays a role during implantation through targeting Wnt4. J Biol Chem. 2014;289(34):23534‐23545.
    1. Williams KC, Renthal NE, Condon JC, Gerard RD, Mendelson CR. MicroRNA‐200a serves a key role in the decline of progesterone receptor function leading to term and preterm labor. Proc Natl Acad Sci USA. 2012;109(19):7529‐7534.
    1. Kelleher AM, Peng W, Pru JK, Pru CA, DeMayo FJ, Spencer TE. Forkhead box a2 (FOXA2) is essential for uterine function and fertility. Proc Natl Acad Sci USA. 2017;114(6):E1018‐e1026.
    1. Yuan J, Cha J, Deng W, et al. Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proc Natl Acad Sci USA. 2016;113(50):e8079‐e8088.
    1. Chen JR, Cheng JG, Shatzer T, Sewell L, Hernandez L, Stewart CL. Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis. Endocrinology. 2000;141(12):4365‐4372.
    1. Park TJ, Mitchell BJ, Abitua PB, Kintner C, Wallingford JB. Dishevelled controls apical docking and planar polarization of basal bodies in ciliated epithelial cells. Nat Genet. 2008;40(7):871‐879.
    1. Rodesch F, Simon P, Donner C, Jauniaux E. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol. 1992;80(2):283‐285.
    1. Dengler VL, Galbraith M, Espinosa JM. Transcriptional regulation by hypoxia inducible factors. Crit Rev Biochem Mol Biol. 2014;49(1):1‐15.
    1. Daikoku T, Matsumoto H, Gupta RA, et al. Expression of hypoxia‐inducible factors in the peri‐implantation mouse uterus is regulated in a cell‐specific and ovarian steroid hormone‐dependent manner. Evidence for differential function of HIFs during early pregnancy. J Biol Chem. 2003;278(9):7683‐7691.
    1. Polanski LT, Baumgarten MN, Quenby S, Brosens J, Campbell BK, Raine‐Fenning NJ. What exactly do we mean by 'recurrent implantation failure'? A systematic review and opinion. Reprod Biomed Online. 2014;28(4):409‐423.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe