Implantation

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Introduction

Human conceptus fully implanted (Stage 5).
Uterine Leukemia Inhibitory Factor (LIF) Expression[1]

The term "implantation" is used to describe process of attachment and invasion of the uterus endometrium by the blastocyst (conceptus) in placental animals. In humans, this process begins at the end of week 1, with most successful human pregnancies the conceptus implants 8 to 10 days after ovulation, and early pregnancy loss increases with later implantation.[2] The implantation process continues through the second week of development.

The initial phase of the implantation process is "adplantation". This first phase requires the newly hatched blastocyst to loosely adhere to the endometrial epithelium, often "rolling" to the eventual site of implantation where it is firmly adhered. This process requires both the blastocyst adhesion interaction with the endometrium during the "receptive window".

Subsequent development of the placenta allows maternal support of embryonic and fetal development. If implantation has not proceeded sufficiently during the menstrual cycle to allow hormonal feedback to the ovary, then the next cycle may commence leading to conceptus loss. There is also evidence, from animal models, that a conceptus with major genetic does not develop or implant correctly leading to their loss during the first and second weeks of development.

In recent years with the development or Assisted Reproductive Technologies (ART or IVF) there is a growing interest in this process, with techniques that introduce the blastocyst into the uterus to allow normal implantation to occur.

Abnormal implantation is where this process does not occur in the body of the uterus (ectopic) or where the placenta forms incorrectly. In addition implantation can occur normally but with an abnormal conceptus, as in a hydatiform mole development.

Implantation Links: implantation | Week 2 | trophoblast | placenta | Lecture - Week 1 and 2 | Implantation Timeline | ectopic pregnancy | hydatidiform mole | placenta abnormalities | Category:Implantation

Some Recent Findings

  • Human Endometrial CD98 Is Essential for Blastocyst Adhesion PMID20976164 | PMC2955532 | PLoS One "These results indicate that CD98, a component of tetraspanin-enriched microdomains, appears to be an important determinant of human endometrial receptivity during the implantation window." OMIM CD98
  • Implantation failure: molecular mechanisms and clinical treatment.[3] "Implantation is a complex initial step in the establishment of a successful pregnancy. Although embryo quality is an important determinant of implantation, temporally coordinated differentiation of endometrial cells to attain uterine receptivity and a synchronized dialog between maternal and embryonic tissues are crucial. The exact mechanism of implantation failure is still poorly understood."
  • Preimplantation factor promotes first trimester trophoblast invasion [4] "Preimplantation factor is a novel embryo-derived peptide that influences key processes in early pregnancy implantation, including immunity, adhesion, remodeling, and apoptosis. Herein, we explore the effects of synthetic preimplantation factor on trophoblast invasion."
  • Mouse trophoblastic cells exhibit a dominant invasiveness phenotype over cancer cells PMID20826050 "We investigated the interactions between trophoblasts and metastatic cancer cells and found the phenomenon that mouse trophoblastic cells invaded the monolayer of malignant cancer cells in vitro and appeared the general trait of invasiveness to more than 30 types of malignant cancer cell lines which were derived from different histological origins and with different invasive or metastatic potential."

Week 1 and 2 Human Development Overview

Week 1 Human Development Overview

Endometrial Receptivity

In humans, receptivity occurs 6 days after the post-ovulatory progesterone surge and lasts about 2 to 4 days. A similar "receptivity window" occurs following fertilization in other species: rat day 5 and mouse day 4.5. Many studies have looked into identifying markers for this receptivity period both to optimise and to block this process.

Implantation Animation

width=250px|height=240px|controller=true|autoplay=false</qt> This animation shows the process of implantation, occurring during week 2 of development in humans.

The beginning of the animation shows: the uterus lining (endometrium epithelium), the hatched blastocyst with a flat outer layer of trophoblast cells (green), the inner cell mass which has formed into the bilaminar embryo (epiblast and hypoblast) and the large fluid-filled space (blastocoel).

green cells - trophoblast layer of the conceptus

blue cells - epiblast layer of the bilaminar embryo

yellow cells - hypoblast layer of the bilaminar embryo

white cells - uterine endometrium epithelium

red - maternal blood vessel

Links: Quicktime version | Flash Version | Quicktime


The second week of human development is concerned with the process of implantation and the differentiation of the blastocyst into early embryonic and placental forming structures.

  • implantation commences about day 6 to 7
  • Adplantation - begins with initial adhesion to the uterine epithelium
    • blastocyst then slows in motility, "rolls" on surface, aligns with the inner cell mass closest to the epithelium and stops
  • Implantation - migration of the blastocyst into the uterine epithelium, process complete by about day 9
  • coagulation plug - left where the blastocyst has entered the uterine wall day 12

Normal Implantation Sites - in uterine wall superior, posterior, lateral

Implantation Factors

Trophinin

  • Trophinin is a membrane protein expressed on blastocyst trophectoderm cells and on uterine endometrium epithelial cells.
  • Adhesion is thought to occur through trophinin-trophinin binding.
  • Adhesion also triggers two trophinin mediated effects:
  1. trophectoderm cells activate for implantation (proliferation, invasion)
  2. maternal endometrial epithelial cells induced programmed cell death (apoptosis).[5]


Links: OMIM

Cytokines

In mice, endometrial secretion of two IL-6 family cytokines, leukemia inhibitory factor (LIF) and Interleukin-11 (IL-11), are key requirements for implantation. A recent human study suggests that there is a similar requirement for human conceptus implantation.[6]

Uterine Leukemia Inhibitory Factor (LIF) Expression[1]

Implantation LIF.jpg

a - At day 4 of pregnancy, oestrogen E2 induces LIF expression in the endometrial glands, leading to LIF secretion into the uterine lumen. There, LIF binds to its receptors on the surface of epithelial cells. b - This makes the uterus receptive to the blastocyst, which implants by day 5 of pregnancy. Hu et al. find that LIF expression in the endometrial glands also depends on the regulatory activity of p53. In the absence of p53, insufficient LIF is produced, the uterus does not become adequately receptive, and fewer blastocysts implant.

Galectin 9

Galectin 9, a protein that binds galactosides and has many different roles, has been identified as a marker for the mid- and late-secretory phases of human endometrium and decidua. The high expression at uterodomes during the period of implantation, suggests that it may also mark endometrial receptivity.[7]


Links: OMIM - eukemia inhibitory factor | OMIM - Interleukin-11 | OMIM - Galectin 9

Pinopods

Scanning electron microscope images of the pig endometrial surface of a day 13 pregnant sow.[8]

(uterodomes) Cellular feature seen on the apical uterine epithelium surface. The presence of these structures is thought in many species to be a marker for endometrial receptivity. In humans though, recent studies have shown pinopodes are also present throughout the luteal phase of the menstrual cycle.[9] It has also been suggested that their role is not primarily pinocytotic, hence the alternate suggested name "uterodomes" based upon their appearance when imaged by electron microscopy.[10]

These transient microprotrusions inter-digitate with microvilli on the apical syncytiotrophoblast surface of the blastocyst during initial adplantation and implantation process.

Day 8 to 9

Gray0032.gif
  • am. - amniotic cavity
  • b.c. - blood clot, at the site of initial implantation
  • b.s. - body-stalk, or connective stalk later forming the placental cord region with placental blood vessels
  • ect. - embryonic ectoderm that will contribute to embryonic and placental membrane development
  • ent. - entoderm (endoderm), this was the historic term for what we today call endoderm that will contribute to embryo development
  • mes. - mesoderm, consisting of both embryonic mesoderm (in the trilaminar embryonic disc) and extraembryonic mesoderm (outside the trilaminar embryonic disc)
  • m.v. - maternal vessels, spiral arteries that have been opened at their ends
  • tr. - trophoblast, relative to the embryonic disc the outer syncitiotrophoblast and inner cytotrophoblast layers that will contribute to placental development
  • u.e. - uterine epithelium, the epithelial layer that lines the unerus
  • u.g. - uterine glands, the glands that secrete nutrients to support the initial growth both before and after implantation
  • y.s. - yolk-sac, the endoderm lined and extraembryonic mesoderm covered cavity that will contribute to the gastrointestinal tract, blood and blood vessels

Decidual Reaction

Placenta anchoring villi

During pregnancy, at implantation the endometrium is altered by the maternal steroid hormones, estrogen and progesterone and in response to the implanting conceptus and renamed the "decidua". This process of signaling is called the decidual reaction or decidualization, and commences at the site of implantation and spreads throughout the uterine lining.

  • occurs within the uterus wall
  • initially at site of implantation and includes both cellular and matrix changes
  • reaction spreads throughout entire uterus, not at cervix
  • promoted by the maternal steroid hormones, estrogen and progesterone
  • extensive proliferation and differentiation of uterine stromal cells
  • deposition of fibrinoid and glycogen and epithelial plaque formation (at anchoring villi)
  • presence of decidual cells are indicative of pregnancy

In uterine stromal decidualization, bone morphogenetic protein 2 (BMP2) nonactive precursor protein is cleaved by proprotein convertase 5/6 (PC6) to produce the active form. Deletion or knockdown of either BMP2 or PC6 inhibits decidualization leads to implantation failure and female infertility.[11]

A recent human histological study has shown that endometrial stromal cell decidualization leads to a loss of lymphatics particularly apparent around the uterine spiral arteries.[12]

Links: OMIM - bone morphogenetic protein 2 | OMIM - proprotein convertase 5

Cervical Mucus Plug

Along with the decidualization, estrogen also stimulates the production of mucus from glands at the opening of the uterus, the cervix, where it joins the vagina. This secreted mucus then forms a plug/barrier (CMP) acting in a mechanical and antibacterial manner.

Abnormal Implantation

Tubal Pregnancy

Ectopic tubal pregnancy

Abnormal implantation sites or Ectopic Pregnancy occurs if implantation is in uterine tube or outside the uterus.

  • sites - external surface of uterus, ovary, bowel, gastrointestinal tract, mesentry, peritoneal wall
  • If not spontaneous then, embryo has to be removed surgically

Tubal pregnancy - 94% of ectopic pregnancies

  • if uterine epithelium is damaged (scarring, pelvic inflammatory disease)
  • if zona pellucida is lost too early, allows premature tubal implantation
  • embryo may develop through early stages, can erode through the uterine horn and reattach within the peritoneal cavity
Tubal pregnancy historic.jpg Abnormal implantation sites.jpg
Links: Ectopic Pregnancy | Movie - Ectopic pregnancy ultrasound


Hydatidiform Mole

Hydatidiform Mole

Another type of abnormality is when only the conceptus trophoblast layers proliferates and not the embryoblast, no embryo develops, this is called a "hydatidiform mole", which is due to the continuing presence of the trophoblastic layer, this abnormal conceptus can also implant in the uterus. The trophoblast cells will secrete human chorionic gonadotropin (hCG), as in a normal pregnancy, and may appear maternally and by pregnancy test to be "normal". Prenatal diagnosis by ultrasound analysis demonstrates the absence of a embryo.

There are several forms of hydatidiform mole: partial mole, complete mole and persistent gestational trophoblastic tumor. Many of these tumours arise from a haploid sperm fertilizing an egg without a female pronucleus (the alternative form, an embryo without sperm contribution, is called parthenogenesis). The tumour has a "grape-like" placental appearance without enclosed embryo formation. Following a first molar pregnancy, there is approximately a 1% risk of a second molar pregnancy.

This topic is also covered in Placenta - Abnormalities

Abnormal Placentation

Placental implantation abnormalities

Abnormalities can range from anatomical associated with degree or site of inplantation, structure (as with twinning), to placental function, placento-maternal effects (pre-eclampsia, fetal erythroblastosis) and finally mechanical abnormalities associated with the placental (umbilical) cord.

This topic is also covered in Placenta - Abnormalities

References

  1. 1.0 1.1 <pubmed>18046411</pubmed>
  2. <pubmed>10362823</pubmed>
  3. <pubmed>20729534</pubmed>
  4. <pubmed>20708167</pubmed>
  5. Tamura N, Sugihara K, Akama TO, Fukuda MN. Trophinin-mediated cell adhesion induces apoptosis of human endometrial epithelial cells through PKC-δ. Cell Cycle. 2011 Jan 1;10(1):135-43 PMID21191175
  6. <pubmed>19213836</pubmed>
  7. <pubmed>18506087</pubmed>
  8. <pubmed>20640155</pubmed>| PMC2904919
  9. <pubmed>18997181</pubmed>
  10. <pubmed>11098008</pubmed>
  11. <pubmed>20555025</pubmed>
  12. <pubmed>20729537</pubmed>

Reviews

<pubmed>21880274</pubmed> <pubmed>18412772</pubmed>

Articles

<pubmed>17495530</pubmed>| PDF

Search PubMed

Search Pubmed: Embryo Adplantation | Embryo Implantation | tubal pregnancy | Endometrial Receptivity | Placenta Abnormalities | Pinopods | decidualization


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Cite this page: Hill, M.A. (2024, March 28) Embryology Implantation. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Implantation

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© Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G