Physiological and molecular determinants of embryo implantation

Abstract

Embryo implantation involves the intimate interaction between an implantation-competent blastocyst and a receptive uterus, which occurs in a limited time period known as the window of implantation. Emerging evidence shows that defects originating during embryo implantation induce ripple effects with adverse consequences on later gestation events, highlighting the significance of this event for pregnancy success. Although a multitude of cellular events and molecular pathways involved in embryo-uterine crosstalk during implantation have been identified through gene expression studies and genetically engineered mouse models, a comprehensive understanding of the nature of embryo implantation is still missing. This review focuses on recent progress with particular attention to physiological and molecular determinants of blastocyst activation, uterine receptivity, blastocyst attachment and uterine decidualization. A better understanding of underlying mechanisms governing embryo implantation should generate new strategies to rectify implantation failure and improve pregnancy rates in women.

Keywords: Blastocyst activation; Blastocyst attachment; Decidualization; Embryo implantation; Uterine receptivity.

Figure 1

Hormonal control of embryo implantation in mice. (A) Steroid hormone patterns are illustrated during indicated days of the estrous cycle, uterine receptivity and early pregnancy. Estrogen secretion (red curve) is high at ovulation after the luteinizing hormone surge. Soon afterwards, progesterone (blue curve) increases beginning in the late afternoon of proestrus. If mating is successful, the newly formed corpora luteum, stimulated by mating behavior, will secrete progesterone from day 3 onward. On day 4, a small surge of estrogen cooperates with progesterone to induce uterine receptivity. Blastocyst implantation occurs at midnight of day 4. After implantation, progesterone is required for decidualization, placentation and completion of pregnancy. (B) Diagrams depicting cross-sections of the preimplantation uterus (Day 1, Day 4) and implantation sites (day 5, day 8). On day 1, the luminal epithelium of the nonreceptive uterus is highly branched. On day 4, the uterus is receptive with the opposing luminal epithelium that closes around an implanting blastocyst. On day 5, the mural trophectoderm of the blastocyst attaches to the antimesometrial luminal epithelium. The stromal cells underlying the invading embryo then proliferate and differentiate to form an avascular primary decidual zone (PDZ) on the afternoon of day 5. Stroma cells next to the PDZ continue proliferation and differentiation to form a well-vascularized secondary decidual zone (SDZ) by day 8. AM, antimesometrial side; Bl, blastocyst; Em, embryo; E₂, estradiol-17β; GE, glandular epithelium; LE, luminal epithelium; M, mesometrial side; P₄, progesterone; S, stroma.

Figure 2

Signals participating in blastocyst activation and uterine epithelial preparation for receptivity. Achievement of blastocyst implantation competency (blastocyst activation) involves steroid signaling, cannabinoid signaling and Wnt signaling pathways. Acquisition of uterine receptivity under the influence of ovarian progesterone and estrogen is associated with a flattening of the luminal epithelium and a loss of polarity at the site of embryo attachment. Several genes regulating uterine transformation are differentially regulated, as illustrated here and detailed in the text. CB1, brain-type cannabinoid receptor-1; ErbB1/4, epidermal growth factor receptor 1/4; ER, estrogen receptor; HB-EGF, heparin-binding EGF-like growth factor; ICM, inner cell mass; Klf5, kruppel-like factor 5; Msx1, muscle segment homeobox 1; 4-OH-E2, 4-hydroxyestradiol; PR, progesterone receptor; Tr, trophectoderm; Wnt5a, wingless-related MMTV integration site 5a.

Figure 3

Signaling networks that regulate embryo implantation. Embryo implantation is a dynamic developmental event which involves physical and physiological interactions among the blastocyst trophectoderm and the uterine luminal and glandular epithelial cells, as well as participation by stromal cells. In this cartoon, critical signals that regulate these interactions are portrayed, as described in the text. AA, arachidonic acid; cPLA2α, cytosolic phospholipase A 2α; COUP-TFII, chicken ovalbumin upstream promoter transcription factor-2; COX2, cyclooxygenase-2; E₂, 17β-estradiol; ER, estrogen receptor; Hand2, Heart- and neural crest derivatives-expressed protein 2; Hoxa10/11, homeobox A10/11; ICM, inner cell mass; LIF, leukemia inhibitory factor; LIFR, LIF receptor; LPA3, lysophosphatidic acid receptor 3; PG, prostaglandin; PPARδ; peroxisome proliferator-activating receptor δ; PR, progesterone receptor; STAT3, signal transducers and activators of Transcription 3; Tr, trophectoderm;.

Figure 4

Synergistic and antagonistic interactions of ovarian progesterone and estrogen on uterine cell proliferation and differentiation. Estrogen-stimulated uterine epithelium proliferation requires the presence of functional ER in the stroma through a paracrine/autocrine manner. Moreover, estrogen-induced differentiation of the uterine epithelium requires ER in both the epithelium and the stroma. Progesterone acts through stromal and epithelial PRs to inhibit the proliferative response of epithelium to estrogen, while inducing the proliferation of the underlying stroma. E₂, 17β-estradiol; ERα, nuclear estrogen receptor-α; LE, luminal epithelium; P₄, progesterone; PF, paracrine factor; PR, progesterone receptor; S, stroma.

Figure 5

Factors governing decidualization and immune tolerance after embryo invasion. Decidualization involves coordination of several processes, including luminal epithelium apoptosis at the site of embryo invasion, epithelial-stromal dialogue initiating decidualization and decidual cell polyploidization. Many molecules, such as cytokine receptors, morphogens, hormones and transcription factors, regulate this process. The primary role of decidua is to protect the genetically ‘foreign’ semi-allogeneic embryo from attack by the maternal immune system. Several immune-related molecules and cells that contribute to decidual development and immune tolerance are depicted in this cartoon and detailed in the text. BMP2, bone morphogenetic protein 2; BTEB1, basic transcription element-binding protein1; COUP-TFII, chicken ovalbumin upstream promoter transcription factor-2; DC: dendritic cell; DEDD, death effector domain-containing protein; ER, estrogen receptor; HB-EGF, heparin-binding EGF-like growth factor; Hoxa10, homeobox A10; Gal1, galectin-1; Hurp, hepatoma upregulated protein; IDO, indoleamine 2,3-dioxygenase 1; IFNγ, interferon γ; Ihh, Indian hedgehog; IL11Ra, interleukin-11 receptor alpha; Klf5, Kruppel-like factor 5; uNK, uterine nature killer cell; PR, progesterone receptor; pRB, retinoblastoma protein; p21, cyclin-dependent kinase inhibitor 1A; Ptch, patched homolog 1; TDO, tryptophan 2,3-dioxygenase ; Wnt4, wingless-related MMTV integration site 4.