6.3 Molecular aspects of implantation

• Introduction
• Signal exchange during preimplantation
• The blastocyst and the uterine epithelium
• Interactions between the blastocyst and endometrium (invasion of the trophoblast)

Introduction

At present the molecular mechanisms of implantation are only partially understood. They evoke complex cascade-like interactions between the embryonic trophoblast cells, epithelial cell, decidual cell, cells responsible for immune reactions and the extra-cellular matrix (ECM) of the maternal endometrium.
These cellular interactions require various mediators such as growth factors, proteinases and their inhibitors, the components of the ECM, adhesion molecules (integrin, cadherin) and hormones.
Decidual cells and the endometrial glands secrete growth factors and various other factors necessary for the implantation of the embryo. For its part the blastocyst secretes its own growth factors and expresses numerous receptors that enable the tissue interactions with the uterine epithelium.

Signal exchange during preimplantation

The embryo and the endometrium communicate with each other already before its apposition at the uterine epithelium. After hatching, the blastocyst secretes molecules that affect ovarian activity, mobility of the fallopian tube and the endometrium (EPF, HCG). With the compaction of the morula, receptors appear for the colony-stimulating factor (CSF), the epidermal growth factor (EGF), the leukocyte inhibitory factor (LIF) and for E-cadherin.
Cadherins are calcium-dependent cell adhesion molecules that play a role in anchoring of the blastocyst in the endometrium. At this stage the embryo also produces interleukin 1 (L-1a und b), which will take on a key role in orienting the embryo toward the endometrium.
The platelet-activating factor (PAF) is also produced by the embryo. Interleukin (IL-1), the receptors for which are localized on the epithelial cells of the endometrium during the secretory phase, is necessary for producing LIF in the uterus.
During the preimplantation phase the density of the surface proteins (glycocalyx) as well as the electrostatic repulsion between the blastocyst and the endometrium decreases, facilitating implantation.

The blastocyst and the uterine epithelium

The apposition and the adhesion of the blastocyst onto the uterine epithelium require the secretion of factors that bind at specific receptors (one of the tissues must secrete ligands, the others should express the receptors).
Numerous "implantation factors" are known:
Interleukin 1 (IL-1), the inhibition factor for leukocytes (LIF), the colony-stimulating factor (CSF), as well as the epithelial growth factor (EGF) and its receptors (EGF-R).

During implantation, embryonic IL-1 binds at its receptors on the surface of the endometrium epithelial cells.

LIF (a glycoprotein that belongs to the cytokine group) is synthesized by the uterine epithelial cells from the 18th day of the menstruation cycle; its receptors are expressed by the blastocyst. It appears to play a role in the differentiation of the CT to ST and assists HCG (human chorionic gonadotropin) secretion.

EGF receptors can bind themselves to numerous ligands. In humans EGF-R are expressed from the 4th day by the cells of the inner cell mass and by the trophoblast. Between the 4th and the 7th day their expression is limited to the inner cell mass and the embryonic pole of the trophoblast. This could be an explanation for the orienting of the blastocyst, which embeds itself in the endometrium with the embryonic pole.

Interactions between the blastocyst and endometrium (invasion of the trophoblast)

The trophoblast behaves like a "pseudo-tumoral tissue" that infiltrates the endometrium. After the basal membrane is destroyed, the trophoblast grows into the decidua of the uterine tissue. Trophoblast cells secrete proteolytically active enzymes that affect the ECM in such a way that it becomes more porous for the invasion of the embryo. These enzymes are mainly matrix metalloproteinase (MMP) and plasminogen-activators.
Trophoblast cells express certain integrins (cell adhesion molecules) on their cell membranes: surface-lying cells express integrins a5b1 and a1b1, which interact with the uterine mucosa, whereas deeper-lying cells display integrin a6 chains.
The growth of the trophoblast into the endometrium and the decomposition of the ECM are controlled by endometrial factors (secreted by epithelial cells, fibroblasts, macrophages and leukocytes). These factors cause autocrine and paracrine effects in order to ease the invasion of the trophoblast. (5)