Mechanisms of implantation: strategies for successful pregnancy

Abstract

Physiological and molecular processes initiated during implantation for pregnancy success are complex but highly organized. This review primarily highlights adverse ripple effects arising from defects during the peri-implantation period that perpetuate throughout pregnancy. These defects are reflected in aberrations in embryo spacing, decidualization, placentation and intrauterine embryonic growth, manifesting in preeclampsia, miscarriages and/or preterm birth. Understanding molecular signaling networks that coordinate strategies for successful implantation and decidualization may lead to approaches to improve the outcome of natural pregnancy and pregnancy conceived from in vitro fertilization.

Figure 1

Signaling network for uterine receptivity and implantation. This is a hybrid cartoon, based on mouse and human studies, portraying compartment- and cell-type– specific expression of molecules and their potential functions necessary for uterine receptivity, implantation and decidualization. Interplay of ovarian P₄- and/or E₂-dependent and P₄- and/or E₂-independent factors in the pregnant uterus in specific compartments contributes to the success of implantation in a juxtacrine/paracrine/autocrine manner. During attachment, interactions between the blastocyst and luminal epithelium (LE) involve ErbB1/4 (blue) and both transmembrane (TM) and soluble (Sol) forms of HB-EGF, as well as L-selectin ligands (sLE) expressed by the luminal epithelium to L-selectin receptors on the blastocyst. The other key signaling pathways for uterine receptivity and implantation are also shown. AA, arachidonic acid; BMP2, bone morphogenetic protein 2; cPLA2α, cytosolic phospholipase A2α; COUP-TFII, chicken ovalbumin upstream promoter transcription factor-2; Cox2, cyclooxygenase-2; E, estrogens; EC, epithelial cell (luminal and glandular epithelia); ENaC, epithelium sodium channel; ER, estrogen receptor; ErbB1/4; epidermal growth factor receptor 1/4; ERK, extracellular signal–regulated kinase; FGF, fibroblast growth factor; GE, glandular epithelium; gp130, glycoprotein 130; Hand2, heart- and neural crest derivatives-expressed protein 2; HB-EGF, heparin-binding epidermal growth factor-like growth factor; Hoxa10/11, homeobox A10/11; ICM, inner cell mass; IHH, Indian hedgehog; KLF5, Kruppel-like factor 5; LIF, leukemia inhibitory factor; LIFR, LIF receptor; LPA3, lysophosphatidic acid receptor 3; MSX1, Muscle segment homeobox 1; P₄, progesterone; PG, prostaglandin; PPAR-δ; peroxisome proliferators–activating receptor δ; PR, progesterone receptor; Ptc, Patched; RXR, retinoid X receptor; SC, stromal cell; SGK1, serum- and glucocorticoid-inducible kinase 1; Smo, Smoothened; STAT3, signal transducer and activator of transcription 3; Tr, trophectoderm; Wnt4/5a, Wingless-Type MMTV integration site family members 4/5a. Compartment colors: blue, stroma; pink, luminal epithelium; orange, glandular epithelium; purple, epithelium at the attachment site.

Figure 2

Signaling networks in decidualization. Key molecules for decidualization are depicted in this hybrid cartoon as gathered from mouse and human studies. The decidua is composed of differentiated stromal (decidual) cells, many of which are terminally differentiated (polyploid). Decidualization involves coordination of several processes, including polyploidy, and several types of molecules, such as cytokine receptors, enzymes, morphogens, hormones and transcription factors. ADM, adrenomedullin; BV, blood vessel; DEDD, death effector domain– containing protein; IL-11Rα, interleukin 11 receptor α; mTORC1, mammalian target of rapamycin complex 1; SGK1, serum- and glucocorticoid-inducible kinase 1; Sphk1/2, sphingosine kinase 1/2.

Figure 3

Potential adverse ripple effects during pregnancy arising from stage-specific defects in mice. (a) Normal pregnancy events encompass receptivity, attachment and implantation, decidualization, and placentation, leading to on-time parturition with full complement of offspring. Defective early pregnancy events veer the remainder of pregnancy off course, leading to adverse outcome. Ptgs2* mutant mice on C57BL/6J/129 genetic background have complete infertility, whereas on a CD1 background they show subfertility due to compensatory upregulation of Ptgs1. (b) Adverse pregnancy events stemming from aberrations in preceding stages in gene-deleted mice. Defective receptivity or deferred implantation (left two stages) results in embryo crowding, conjoined placenta, placental insufficiency, fetal growth restriction, fetal resorption and reduced litter size, whereas suboptimal decidualization (third stage) can lead to premature decidual senescence, resulting in preterm birth with neonatal death, or in abnormal guidance of placentation, which can lead to shallow invasion and preeclampsia. ADM, adrenomedullin; bl, blastocyst; CB1, cannabinoid receptor 1; Cox2, cyclooxygenase-2; cPLA2α, cytosolic phospholipase A2α; DB, decidua basalis; DC, decidua capsularis; dec, decidua; emb, embryo; EPC, ectoplacental cone; Klf5, Kruppel-like factor 5; LPA3, lysophosphatidic acid 3; Msx1, muscle segment homeobox 1; mTORC1, mammalian target of rapamycin complex 1; myo, myometrium; p53, transformation-related protein p53; Sgk1, serum- and glucocorticoid-inducible kinase 1; Sp, spongiotrophoblast.

Figure 4

Plausible charting of adverse ripple effects in human pregnancy. Defective receptivity, implantation, and/or decidualization can lead to infertility. Deferred implantation past the window of receptivity can lead to misguided embryo placement and implantation, resulting in placenta previa, ectopic placentation (placenta accreta) or placental insufficiency resulting in intrauterine growth restriction (IUGR) and/or preeclampsia. Implantation beyond the normal window can also give rise to spontaneous abortion, miscarriage and recurrent pregnancy loss, leading to infertility. Premature decidual senescence can lead to preterm birth and fetal death, whereas shallow trophoblast invasion into maternal decidua and/or blood vessels can lead to preeclampsia.