Implantation
Encyclopedia
In humans, implantation is the beginning of pregnancy
, in which the embryo
Adheres to the wall of the uterus
. At this stage of prenatal development, the embryo is a blastocyst
. It is by this adhesion that the fetus receives the oxygen and the nutrients from the mother to be able to grow.
Implantation occurs about 9 days after ovulation
, ranging between 6 to 12 days.
rather than the continued gestation of a malformed fetus.
The implantation window is started by preparations in the endometrium
of the uterus, both structurally and in the composition of its secretions.
and its glands grow to be tortuous and boosted in their secretions. These changes reach their maximum about 7 days after ovulation
.
Furthermore, the surface of the endometrium produces a kind of rounded cells, which cover the whole area toward the uterine cavity. This happens about 9 to 10 days after ovulation. These cells are called decidual cells, which emphasises that the whole layer of them is shed off in every menstruation
if no pregnancy occurs, just as leaves of deciduous trees. The uterine glands, on the other hand, decrease in activity and degenerate already 8 to 9 days after ovulation in absence of pregnancy.
The stromal cell
s originate from the stromal cells that are always present in the endometrium. However, the decidual cells make up a new layer, the decidua
. The rest of the endometrium, in addition, expresses differences between the luminal and the basal sides. The luminal cells form the zona compacta of the endometrium, in contrast to the basalolateral zona spongiosa, which consists of the rather spongy stromal cells.
. However, some elements of the decidualization remain throughout pregnancy.
The compacta and spongiosa layers are still observable beneath the decidua in pregnancy. The glands of the spongiosa layer continue to secrete during the first trimester, when they degenerate. However, before that disappearance, some glands secrete unequally much. This phenomenon of hypersecretion is called the Arias-Stella phenomenon, after the pathologist Javier Arias-Stella.
. This corresponds to a fertilization age of approximately 5 to 7 days, which corresponds well with the time of implantation. They only persist for 2 to 3 days. The development of them is enhanced by progesterone
but inhibited by estrogens.
| proteins, glycoproteins and peptides
secreted by the endometrial glands
|-
| Matrix
-associated:
|-
| Fibronectin
|-
| Laminin
|-
| Entactin
|-
| Type-IV collagen
|-
| heparan sulfate
|-
| Proteoglycan
|-
| Integrins
|-
| -
|-
| Others:
|-
| Mucin
s
|-
| Prolactin
|-
| IGFBP-1
|-
| Placental protein 14 (PP14) or glycodelin
|-
| Pregnancy-associated endometrial
alpha-2-globulin (alpha-2-PEG)
|-
| endometrial protein 15
|-
| Albumin
|-
| Beta-Lipoprotein
|-
| Relaxin
|-
| Fibroblast growth factor 1
|-
| Fibroblast growth factor 2
|-
| Pregnancy-associated plasma protein A
(PAPP-A)
|-
| Stress response protein 27 (SRP-27)
|-
| CA-125
|-
| Beta-endorphin
|-
| Leu-enkephalin
|-
| Diamine oxidase
|-
| Tissue plasminogen activator
|-
| Renin
|-
| Progesterone-dependent carbonic anhydrase
|-
| Lactoferrin
|-
|}>
Not only the lining of the uterus transforms. In addition, the secretion from its epithelial glands changes. This change is induced by increased levels of progesterone
from the corpus luteum
. The target of the secretions is the embryoblast, and has several functions on it.
-dependent proteins, important for growth and implantation. Cholesterol
and steroids are also secreted. Implantation is further facilitated by synthesis of matrix
substances, adhesion molecules and surface receptors
for the matrix substances.
. This process can be called "hatching".
. Plasminogen, the plasmin precursor, is found in the uterine cavity, and blastocyst factors contribute to its conversion to active plasmin. This hypothesis is supported by lytic effects in vitro
by plasmin. Furthermore, plasmin inhibitors also inhibit the entire zona hatching in rat experiments.
On the blastocyst, on the other hand, it occurs at a location where there has been enough lysis of the zona pellucida to have created a rupture to enable direct contact between the underlying trophoblast
and the decidua of the endometrium. However, ultimately, the inner cell mass
, inside the trophoblast
layer, is aligned closest to the decidua. Nevertheless, the apposition on the blastocyst is not dependent on if it is on the same side of the blastocyst as the inner cell mass. Rather, the inner cell mass rotates inside the trophoblast to align to the apposition. In short, the entire surface of the blastocyst has a potential to form the apposition to the decidua.
The trophoblasts adhere by penetrating the endometrium, with protrusions of trophoblast cells.
of decidual cells. This, in turn, dislodges the decidual cells from their connection to the underlying basal lamina
, which enables the blastocyst to perform the succeeding invasion.
This communication is conveyed by receptor
-ligand
-interactions, both integrin-matrix and proteoglycan ones.
Another ligand-receptor system involved in adhesion is proteoglycan receptors, found on the surface of the decidua of the uterus. Their counterparts, the proteoglycans, are found around the trophoblast cells of the blastocyst. This ligand-receptor system also is present just at the implantation window.
. The prefix syn- refers to the transformation that occurs as the boundaries between these cells disappear to form a single mass of many cell nuclei
(a syncytium
). The rest of the trophoblasts, surrounding the inner cell mass, are hereafter called cytotrophoblast
s.
Invasion continues with the syncytiotrophoblasts reaching the basal membrane beneath the decidual cells, penetrating it and further invading into the uterine stroma. Finally, the whole embryo is embedded in the endometrium. Eventually, the syncytiotrophoblasts come into contact with maternal blood and form chorionic villi
. This is the initiation of forming the placenta
.
Human chorionic gonadotropin
is an autocrine growth factor for the blastocyst. Insulin-like growth factor
type 2, on the other hand, stimulates the invasiveness of it.
The syncytiotrophoblasts dislodges decidual cells in their way, both by degradation of cell adhesion molecule
s linking the decidual cells together as well as degradation of the extracellular matrix between them.
Cell adhesion molecules are degraded by syncytiotrophoblast secretion of Tumor necrosis factor-alpha. This inhibits the expression of cadherins and beta-catenin
. Cadherins is a cell adhesion molecule and beta-catenin helps to anchor it to the cell membrane. Inhibited expression of these molecules thus loosens the connection between decidual cells, permitting the syncytotrophoblasts and the whole embryo with them to invade into the endometrium.
The extracellular matrix is degraded by serine endopeptidases and metalloproteinase
s. Examples of such metalloproteinases are collagenases
, gelatinases and stromelysins. These collagenases digest Type-I collagen
, Type-II collagen
, Type-III collagen
, Type-VII collagen and Type-X collagen. The gelatinases exist in two forms; one digesting Type-IV collagen
and one digesting gelatin
.
The embryo differs from the cells of the mother, and would be rejected as a parasite by the immune system
of the mother if it didn't secrete immunosuppressive agents. Such agents are Platelet-activating factor
, human chorionic gonadotropin
, early pregnancy factor
, immunosuppressive factor, Prostaglandin E
2, Interleukin 1-alpha, Interleukin 6
, interferon
-alpha, leukemia inhibitory factor
and Colony-Stimulating Factor
.
Factors from the blastocyst also trigger the final formation of decidual cells into their proper form. In contrast, some decidual cells in the proximity of the blastocyst degenerate, providing nutrients for it.
Human chorionic gonadotropin
(hCG) not only acts as an immunosuppressive, but also "notifies" the mother's body that she is pregnant, preventing menstruation by sustaining the function of the corpus luteum
.
Other factors secreted by the blastocyst are;
and hormonal signaling as well as epigenetic alterations. Recurrent implantation failure is a cause of female infertility
. Therefore, pregnancy rate
s can be improved by optimizing endometrial receptivity for implantation. Evaluation of implantation markers may help to predict pregnancy outcome and detect occult implantation deficiency.
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
, in which the embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
Adheres to the wall of the uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
. At this stage of prenatal development, the embryo is a blastocyst
Blastocyst
The blastocyst is a structure formed in the early embryogenesis of mammals, after the formation of the morula. It is a specifically mammalian example of a blastula. It possesses an inner cell mass , or embryoblast, which subsequently forms the embryo, and an outer layer of cells, or trophoblast,...
. It is by this adhesion that the fetus receives the oxygen and the nutrients from the mother to be able to grow.
Implantation occurs about 9 days after ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
, ranging between 6 to 12 days.
The implantation window
There are many conditions that must be satisfied in order for a successful implantation to take place. There is only a specific period of time during which implantation is possible; this is the "implantation window". A reason for this window is that if implantation does not occur at a certain time, then it signifies that something is wrong. And when there is a risk that something is wrong, there will most likely be a miscarriageMiscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
rather than the continued gestation of a malformed fetus.
The implantation window is started by preparations in the endometrium
Endometrium
-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
of the uterus, both structurally and in the composition of its secretions.
Adaption of uterus
To enable implantation, the uterus goes through changes in order to be able to receive the embryo.Predecidualization
The endometrium increases thickness, becomes more vascularizedAngiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
and its glands grow to be tortuous and boosted in their secretions. These changes reach their maximum about 7 days after ovulation
Ovulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
.
Furthermore, the surface of the endometrium produces a kind of rounded cells, which cover the whole area toward the uterine cavity. This happens about 9 to 10 days after ovulation. These cells are called decidual cells, which emphasises that the whole layer of them is shed off in every menstruation
Menstruation
Menstruation is the shedding of the uterine lining . It occurs on a regular basis in sexually reproductive-age females of certain mammal species. This article focuses on human menstruation.-Overview:...
if no pregnancy occurs, just as leaves of deciduous trees. The uterine glands, on the other hand, decrease in activity and degenerate already 8 to 9 days after ovulation in absence of pregnancy.
The stromal cell
Stromal cell
In cell biology, stromal cells are connective tissue cells of any organ, for example in the uterine mucosa , prostate, bone marrow, and the ovary. They are cells that support the function of the parenchymal cells of that organ...
s originate from the stromal cells that are always present in the endometrium. However, the decidual cells make up a new layer, the decidua
Decidua
Decidua is the term for the uterine lining during a pregnancy, which forms the maternal part of the placenta. It is formed under the influence of progesterone and forms highly-characteristic cells.-Etymology:...
. The rest of the endometrium, in addition, expresses differences between the luminal and the basal sides. The luminal cells form the zona compacta of the endometrium, in contrast to the basalolateral zona spongiosa, which consists of the rather spongy stromal cells.
Decidualization
Decidualization succeeds predecidualization if pregnancy occurs. This is an expansion of it, further developing the uterine glands, the zona compacta and the epithelium of decidual cells lining it. The decidual cells become filled with lipids and glycogen and take the polyhedral shape characteristic for decidual cells.Trigger
It is likely that the blastocyst itself makes the main contribution to this additional growing and sustaining of the decidua. An indication of this is that decidualization occurs at a higher degree in conception cycles than in nonconception cycles. Furthermore, similar changes are observed when giving stimuli mimicking the natural invasion of the embryo.Parts of decidua
The decidua can be organized into separate sections, although they have the same composition.- Decidua basalis - This is the part of the decidua which is located basalolateral to the embryo after implantation.
- Decidua capsularis - Decidua capsularis grows over the embryo on the luminal side, enclosing it into the endometrium. It surrounds the embryo together with decidua basalis.
- Decidua Parietalis - All other decidua on the uterine surface belongs to decidua parietalis.
Decidua throughout pregnancy
After implantation the decidua remains, at least through the first trimester. However, its most prominent time is during the early stages of pregnancy, during implantation. Its function as a surrounding tissue is replaced by the definitive placentaPlacenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
. However, some elements of the decidualization remain throughout pregnancy.
The compacta and spongiosa layers are still observable beneath the decidua in pregnancy. The glands of the spongiosa layer continue to secrete during the first trimester, when they degenerate. However, before that disappearance, some glands secrete unequally much. This phenomenon of hypersecretion is called the Arias-Stella phenomenon, after the pathologist Javier Arias-Stella.
Pinopodes
Pinopodes are small, finger-like protrusions from the endometrium. They appear between day 19 and day 21 of gestational ageGestational age
Gestational age relates to the age of an embryo or fetus . There is some ambiguity in how it is defined:*In embryology, gestational age is the time elapsed since conception. This interval is also termed fertilisation age....
. This corresponds to a fertilization age of approximately 5 to 7 days, which corresponds well with the time of implantation. They only persist for 2 to 3 days. The development of them is enhanced by progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
but inhibited by estrogens.
Function in implantation
Pinopodes endocytose uterine fluid and macromolecules in it. By doing so, the volume of the uterus decreases, taking the walls closer to the embryoblast floating in it. Thus, the period of active pinocytes might also limit the implantation window.Function during implantation
Pinopodes continue to absorb fluid, and removes most of it during the early stages of implantation.Adaption of secretions
secreted by the endometrial glands
|-
| Matrix
Matrix (biology)
In biology, matrix is the material between animal or plant cells, in which more specialized structures are embedded, and a specific part of the mitochondrion that is the site of oxidation of organic molecules. The internal structure of connective tissues is an extracellular matrix...
-associated:
|-
| Fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
|-
| Laminin
Laminin
Laminins are major proteins in the basal lamina , a protein network foundation for most cells and organs...
|-
| Entactin
Entactin
Entactin also known as nidogen-1 is a protein that in humans is encoded by the NID1 gene. Entactin is a component of the basement membrane alongside other components such as collagen type IV, proteoglycans , laminin and fibronectin.- Function :Entactin is a member of the nidogen family of basement...
|-
| Type-IV collagen
Type-IV collagen
Type-IV collagen is a type of collagen found primarily in the basal lamina. The type IV collagen C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, type-IV lacks the regular glycine in every third residue...
|-
| heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
|-
| Proteoglycan
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
|-
| Integrins
|-
| -
|-
| Others:
|-
| Mucin
Mucin
Mucins are a family of high molecular weight, heavily glycosylated proteins produced by epithelial tissues in most metazoans. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most gel-like secretions, serving functions from lubrication to cell...
s
|-
| Prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
|-
| IGFBP-1
|-
| Placental protein 14 (PP14) or glycodelin
|-
| Pregnancy-associated endometrial
alpha-2-globulin (alpha-2-PEG)
|-
| endometrial protein 15
|-
| Albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
|-
| Beta-Lipoprotein
|-
| Relaxin
Relaxin
Relaxin is a protein hormone first described in 1926 by Frederick Hisaw.The relaxin-like peptide family belongs in the insulin superfamily and consists of 7 peptides of high structural but low sequence similarity; relaxin-1 , 2 and 3 , and the insulin-like peptides, INSL3, INSL4, INSL5 and INSL6...
|-
| Fibroblast growth factor 1
|-
| Fibroblast growth factor 2
|-
| Pregnancy-associated plasma protein A
Pregnancy-associated plasma protein A
Pregnancy-associated plasma protein A, pappalysin 1, also known as PAPPA, is a protein used in screening tests for Down syndrome.This gene encodes a secreted metalloproteinase which cleaves insulin-like growth factor binding proteins . It is thought to be involved in local proliferative processes...
(PAPP-A)
|-
| Stress response protein 27 (SRP-27)
|-
| CA-125
CA-125
CA-125 also known as mucin 16 or MUC16 is a protein that in humans is encoded by the MUC16 gene. MUC16 is a member of the mucin family glycoproteins...
|-
| Beta-endorphin
Beta-endorphin
β-endorphin is an endogenous opioid peptide neurotransmitter found in the neurons of both the central and peripheral nervous system.The amino acid sequence is:...
|-
| Leu-enkephalin
Enkephalin
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, or specifically endorphins, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin were revealed, one...
|-
| Diamine oxidase
Amine oxidase
Amine oxidase is an enzyme involved in the metabolism of histamine.-External links:...
|-
| Tissue plasminogen activator
Tissue plasminogen activator
Tissue plasminogen activator is a protein involved in the breakdown of blood clots. It is a serine protease found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown...
|-
| Renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
|-
| Progesterone-dependent carbonic anhydrase
Carbonic anhydrase
The carbonic anhydrases form a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons , a reversible reaction that occurs rather slowly in the absence of a catalyst...
|-
| Lactoferrin
Lactoferrin
Lactoferrin , also known as lactotransferrin , is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions...
|-
|}>
Not only the lining of the uterus transforms. In addition, the secretion from its epithelial glands changes. This change is induced by increased levels of progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
from the corpus luteum
Corpus luteum
The corpus luteum is a temporary endocrine structure in mammals, involved in production of relatively high levels of progesterone and moderate levels of estradiol and inhibin A...
. The target of the secretions is the embryoblast, and has several functions on it.
Nourishment
The embryoblast spends approximately 72 hours in the uterine cavity before implanting. In that time, it cannot receive nourishment directly from the blood of the mother, and must rely on secreted nutrients into the uterine cavity, e.g. iron and fat-soluble vitamins.Growth and implantation
In addition to nourishment, the endometrium secretes several steroidSteroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
-dependent proteins, important for growth and implantation. Cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
and steroids are also secreted. Implantation is further facilitated by synthesis of matrix
Matrix (biology)
In biology, matrix is the material between animal or plant cells, in which more specialized structures are embedded, and a specific part of the mitochondrion that is the site of oxidation of organic molecules. The internal structure of connective tissues is an extracellular matrix...
substances, adhesion molecules and surface receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
for the matrix substances.
Mechanism
Implantation is initiated when the blastocyst comes into contact with the uterine wall.Zona hatching
To be able to perform implantation, the blastocyst first needs to get rid of its zona pellucidaZona pellucida
The zona pellucida is a glycoprotein membrane surrounding the plasma membrane of an oocyte. It is a vital constitutive part of the latter, external but of essential importance to it...
. This process can be called "hatching".
Factors
Lytic factors in the uterine cavity, as well as factors from the blastocyst itself are essential for this process. Mechanisms in the latter are indicated by that the zona pellucida remains intact if an unfertilized egg is placed in the uterus under the same conditions. A substance probably involved is plasminPlasmin
Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, most notably, fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.- Function :...
. Plasminogen, the plasmin precursor, is found in the uterine cavity, and blastocyst factors contribute to its conversion to active plasmin. This hypothesis is supported by lytic effects in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
by plasmin. Furthermore, plasmin inhibitors also inhibit the entire zona hatching in rat experiments.
Apposition
The very first, albeit loose, connection between the blastocyst and the endometrium is called the apposition.Location
On the endometrium, the apposition is usually made where there is a small crypt in it, perhaps because it increases the area of contact with the rather spherical blastocyst.On the blastocyst, on the other hand, it occurs at a location where there has been enough lysis of the zona pellucida to have created a rupture to enable direct contact between the underlying trophoblast
Trophoblast
Trophoblasts are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and develop into a large part of the placenta. They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg...
and the decidua of the endometrium. However, ultimately, the inner cell mass
Inner cell mass
In early embryogenesis of most eutherian mammals, the inner cell mass is the mass of cells inside the primordial embryo that will eventually give rise to the definitive structures of the fetus...
, inside the trophoblast
Trophoblast
Trophoblasts are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and develop into a large part of the placenta. They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg...
layer, is aligned closest to the decidua. Nevertheless, the apposition on the blastocyst is not dependent on if it is on the same side of the blastocyst as the inner cell mass. Rather, the inner cell mass rotates inside the trophoblast to align to the apposition. In short, the entire surface of the blastocyst has a potential to form the apposition to the decidua.
Adhesion
Adhesion is a much stronger attachment to the endometrium than the loose apposition.The trophoblasts adhere by penetrating the endometrium, with protrusions of trophoblast cells.
Communication
There is massive communication between the blastocyst and the endometrium at this stage. The blastocyst signals to the endometrium to adapt further to its presence, e.g. by changes in the cytoskeletonCytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
of decidual cells. This, in turn, dislodges the decidual cells from their connection to the underlying basal lamina
Basal lamina
The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often confused with the basement membrane, and sometimes used inconsistently in the literature, see below....
, which enables the blastocyst to perform the succeeding invasion.
This communication is conveyed by receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
-ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
-interactions, both integrin-matrix and proteoglycan ones.
proteoglycan receptors
Another ligand-receptor system involved in adhesion is proteoglycan receptors, found on the surface of the decidua of the uterus. Their counterparts, the proteoglycans, are found around the trophoblast cells of the blastocyst. This ligand-receptor system also is present just at the implantation window.
Syncytiotrophoblasts
The protrusions of trophoblast cells that adhere into the endometrium continue to proliferate and penetrate into the endometrium. As these trophoblast cells penetrate, they differentiate to become a new type of cells, syncytiotrophoblastSyncytiotrophoblast
Syncytiotrophoblast is the epithelial covering of the placenta villous tree. It is a unique tissue in that it is a multi-nucleated, terminally differentiated syncytium, extending to 13m^2...
. The prefix syn- refers to the transformation that occurs as the boundaries between these cells disappear to form a single mass of many cell nuclei
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
(a syncytium
Syncytium
In biology, a syncytium is a large cell-like structure; filled with cytoplasm and containing many nuclei. Most cells in eukaryotic organisms have a single nucleus; syncytia are specialized forms used by various organisms.The term may also refer to cells that are connected by specialized membrane...
). The rest of the trophoblasts, surrounding the inner cell mass, are hereafter called cytotrophoblast
Cytotrophoblast
The cytotrophoblast is the inner layer of the trophoblast, interior to the syncytiotrophoblast in an embryo.Cytotrophoblast is considered to be the trophoblastic stem cell; it differentiates into the other forms of trophoblastic tissue .-External links: - "Female Reproductive System: placental...
s.
Invasion continues with the syncytiotrophoblasts reaching the basal membrane beneath the decidual cells, penetrating it and further invading into the uterine stroma. Finally, the whole embryo is embedded in the endometrium. Eventually, the syncytiotrophoblasts come into contact with maternal blood and form chorionic villi
Chorionic villi
Chorionic villi are villi that sprout from the chorion in order to give a maximum area of contact with the maternal blood.Embryonic blood is carried to the villi by the branches of the umbilical arteries, and after circulating through the capillaries of the villi, is returned to the embryo by the...
. This is the initiation of forming the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
.
Secretions
The blastocyst secretes factors for a multitude of purposes during invasion. It secretes several autocrine factors, targeting itself and stimulating it to further invade the endometrium. Furthermore, secretions loosen decidual cells from each other, prevent the embryo from being rejected by the mother, trigger the final decidualization and prevent menstruation.Autocrine
Human chorionic gonadotropin
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
is an autocrine growth factor for the blastocyst. Insulin-like growth factor
Insulin-like growth factor
The insulin-like growth factors are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment...
type 2, on the other hand, stimulates the invasiveness of it.
Dislodging
The syncytiotrophoblasts dislodges decidual cells in their way, both by degradation of cell adhesion molecule
Cell adhesion molecule
Cell Adhesion Molecules are proteins located on the cell surface involved with the binding with other cells or with the extracellular matrix in the process called cell adhesion....
s linking the decidual cells together as well as degradation of the extracellular matrix between them.
Cell adhesion molecules are degraded by syncytiotrophoblast secretion of Tumor necrosis factor-alpha. This inhibits the expression of cadherins and beta-catenin
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
. Cadherins is a cell adhesion molecule and beta-catenin helps to anchor it to the cell membrane. Inhibited expression of these molecules thus loosens the connection between decidual cells, permitting the syncytotrophoblasts and the whole embryo with them to invade into the endometrium.
The extracellular matrix is degraded by serine endopeptidases and metalloproteinase
Metalloproteinase
Metalloproteinases constitute a family of enzymes from the group of proteases, classified by the nature of the most prominent functional group in their active site. These are proteolytic enzymes whose catalytic mechanism involves a metal. Most metalloproteases are zinc-dependent, but some use...
s. Examples of such metalloproteinases are collagenases
Collagenases
Collagenases are enzymes that break the peptide bonds in collagen.They assist in destroying extracellular structures in pathogenesis of bacteria such as Clostridium. They are an exotoxin and help to facilitate the spread of gas gangrene...
, gelatinases and stromelysins. These collagenases digest Type-I collagen
Type-I collagen
Type-I collagen is the most abundant collagen of the human body.It is present in scar tissue, the end product when tissue heals by repair.It is found in tendons, the endomysium of myofibrils and the organic part of bone.- See also :* Collagen...
, Type-II collagen
Type-II collagen
Type-II collagen is the basis for articular cartilage and hyaline cartilage.It makes up 50% of all protein in cartilage and 85-90% of collagen of articular cartilage....
, Type-III collagen
Type-III collagen
Collagen alpha-1 chain is a protein that in humans is encoded by the COL3A1 gene, which is located on chromosome 2.- Function :Collagen alpha-1 chain is a fibrillar collagen that is found in extensible connective tissues such as skin, lung, and the vascular system, frequently in association with...
, Type-VII collagen and Type-X collagen. The gelatinases exist in two forms; one digesting Type-IV collagen
Type-IV collagen
Type-IV collagen is a type of collagen found primarily in the basal lamina. The type IV collagen C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, type-IV lacks the regular glycine in every third residue...
and one digesting gelatin
Gelatin
Gelatin is a translucent, colorless, brittle , flavorless solid substance, derived from the collagen inside animals' skin and bones. It is commonly used as a gelling agent in food, pharmaceuticals, photography, and cosmetic manufacturing. Substances containing gelatin or functioning in a similar...
.
Immunosuppressive
The embryo differs from the cells of the mother, and would be rejected as a parasite by the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
of the mother if it didn't secrete immunosuppressive agents. Such agents are Platelet-activating factor
Platelet-activating factor
Platelet-activating factor, also known as a PAF, PAF-acether or AGEPC is a potent phospholipid activator and mediator of many leukocyte functions, including platelet aggregation and degranulation, inflammation, and anaphylaxis...
, human chorionic gonadotropin
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
, early pregnancy factor
Early pregnancy factor
Early pregnancy factor or early conception factor is a protein associated with mammalian embryos shortly after fertilization. It may be composed of more than one molecule. It was first described in 1976.-Detection:...
, immunosuppressive factor, Prostaglandin E
Prostaglandin E
Prostaglandin E is a family of naturally occurring prostaglandins and may be used pharmaceutically in medicine.Types include:* Prostaglandin E1 also termed Alprostadil* Prostaglandin E2 also termed DinoprostoneIt is created from prostaglandin E synthase....
2, Interleukin 1-alpha, Interleukin 6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
-alpha, leukemia inhibitory factor
Leukemia inhibitory factor
Leukemia inhibitory factor, or LIF, an interleukin 6 class cytokine, is a protein in cells that affects cell growth and development.-Function:LIF derives its name from its ability to induce the terminal differentiation of myeloid leukemic cells...
and Colony-Stimulating Factor
Colony-stimulating factor
Colony-stimulating factors are secreted glycoproteins that bind to receptor proteins on the surfaces of hemopoietic stem cells, thereby activating intracellular signaling pathways that can cause the cells to proliferate and differentiate into a specific kind of blood cell Colony-stimulating...
.
Decidualization
Factors from the blastocyst also trigger the final formation of decidual cells into their proper form. In contrast, some decidual cells in the proximity of the blastocyst degenerate, providing nutrients for it.
Prevention of menstruation
Human chorionic gonadotropin
Human chorionic gonadotropin
Human chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
(hCG) not only acts as an immunosuppressive, but also "notifies" the mother's body that she is pregnant, preventing menstruation by sustaining the function of the corpus luteum
Corpus luteum
The corpus luteum is a temporary endocrine structure in mammals, involved in production of relatively high levels of progesterone and moderate levels of estradiol and inhibin A...
.
Other factors
Other factors secreted by the blastocyst are;
- ovum factor
- Embryo-derived histamine-releasing factor
- Tissue plasminogen activatorTissue plasminogen activatorTissue plasminogen activator is a protein involved in the breakdown of blood clots. It is a serine protease found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown...
as well as its inhibitors - EstradiolEstradiolEstradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
- β1-integrinIntegrinIntegrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
s - Fibroblast growth factorFibroblast growth factorFibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal...
- Transforming growth factor alpha
- inhibin
Failure
has diverse causes, including abnormal cytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
and hormonal signaling as well as epigenetic alterations. Recurrent implantation failure is a cause of female infertility
Female infertility
-Causes and factors:Causes or factors of female infertility can basically be classified regarding whether they are acquired or genetic, or strictly by location.-Acquired versus genetic:...
. Therefore, pregnancy rate
Pregnancy rate
Pregnancy rate in infertility treatment is the success rate for pregnancy. It is the percentage of all attempts that leads to pregnancy, with attempts generally referring to menstrual cycles where insemination or any artificial equivalent is used, which may be simple artificial insemination or AI...
s can be improved by optimizing endometrial receptivity for implantation. Evaluation of implantation markers may help to predict pregnancy outcome and detect occult implantation deficiency.