Human embryonic

development

Human embryonic development, or human embryogenesis, is the development and formation of the
human embryo. It is characterised by the processes of cell division and cellular differentiation of the
embryo that occurs during the early stages of development. In biological terms, the development of
the human body entails growth from a one-celled zygote to an adult human being. Fertilization
occurs when the sperm cell successfully enters and fuses with an egg cell (ovum). The genetic
material of the sperm and egg then combine to form the single cell zygote and the germinal stage of
development commences.[1] Embryonic development in the human, covers the first eight weeks of
development; at the beginning of the ninth week the embryo is termed a fetus. Human embryology is
the study of this development during the first eight weeks after fertilization. The normal period of
gestation (pregnancy) is about nine months or 40 weeks.
The initial stages of human embryonic development (embryogenesis)

The germinal stage refers to the time from fertilization through the development of the early
embryo until implantation is completed in the uterus. The germinal stage takes around 10 days.[2]
During this stage, the zygote begins to divide, in a process called cleavage. A blastocyst is then
formed and implants in the uterus. Embryogenesis continues with the next stage of gastrulation,
when the three germ layers of the embryo form in a process called histogenesis, and the processes
of neurulation and organogenesis follow.

In comparison to the embryo, the fetus has more recognizable external features and a more
complete set of developing organs. The entire process of embryogenesis involves coordinated
spatial and temporal changes in gene expression, cell growth and cellular differentiation. A nearly
identical process occurs in other species, especially among chordates.

Germinal stage

Fertilization

Fertilization takes place when the spermatozoon has successfully entered the ovum and the two sets
of genetic material carried by the gametes fuse together, resulting in the zygote (a single diploid
cell). This usually takes place in the ampulla of one of the fallopian tubes. The zygote contains the
combined genetic material carried by both the male and female gametes which
consists of the 23 chromosomes from the nucleus of the ovum and the 23 chromosomes from the
nucleus of the sperm. The 46 chromosomes undergo changes prior to the mitotic division which
leads to the formation of the embryo having two cells.

Successful fertilization is enabled by three processes, which also act as controls to ensure species-
specificity. The first is that of chemotaxis which directs the movement of the sperm towards the
ovum.[3] Secondly, an adhesive compatibility between the sperm and the egg occurs. With the sperm
adhered to the ovum, the third process of acrosomal reaction takes place; the front part of the
spermatozoan head is capped by an acrosome which contains digestive enzymes to break down the
zona pellucida and allow its entry.[4] The entry of the sperm causes calcium to be released which
blocks entry to other sperm cells.[4] A parallel reaction takes place in the ovum called the zona
reaction. This sees the release of cortical granules that release enzymes which digest sperm receptor
proteins, thus preventing polyspermy.[5] The granules also fuse with the plasma membrane and
modify the zona pellucida in such a way as to prevent further sperm entry.

Cleavage

Eight-cell embryo, at three days

The beginning of the cleavage process is marked when the zygote divides through mitosis into two
cells. This mitosis continues and the first two cells divide into four cells, then into eight cells and so
on. Each division takes from 12 to 24 hours. The zygote is large compared to any other cell and
undergoes cleavage without any overall increase in size. This means that with each successive
subdivision, the ratio of nuclear to cytoplasmic material increases. [6]
Initially, the dividing cells, called blastomeres (blastos Greek for sprout), are undifferentiated and
aggregated into a sphere enclosed within the zona pellucida of the ovum. When eight blastomeres
have formed, they start to compact.[7] They begin to develop gap junctions, enabling them to develop
in an integrated way and co-ordinate their response to physiological signals and environmental
cues.[8]

When the cells number around sixteen, the solid sphere of cells within the zona pellucida is
referred to as a morula.[9]

Blastulation

Blastocyst with an inner cell mass and trophoblast

Cleavage itself is the first stage in blastulation, the process of forming the blastocyst. Cells
differentiate into an outer layer of cells called the trophoblast, and an inner cell mass. With further
compaction the individual outer blastomeres, the trophoblasts, become indistinguishable. They are
still enclosed within the zona pellucida. This compaction serves to make the structure watertight,
containing the fluid that the cells will later secrete. The inner mass of cells differentiate to become
embryoblasts and polarise at one end. They close together and form gap junctions, which facilitate
cellular communication. This polarisation leaves a cavity, the blastocoel, creating a structure that is
now termed the blastocyst. (In animals other than mammals, this is called the blastula). The
trophoblasts secrete fluid into the blastocoel.
The resulting increase in size of the blastocyst causes it to hatch through the zona pellucida, which
then disintegrates.[6] This process is called zona hatching and it takes place on the sixth day of
embryo development, immediately before the implantation process. The hatching of the human
embryo is supported by proteases secreted by the cells of the blastocyst, which digest
proteins of the zona pellucida, giving rise to a hole. Then, due to the rhythmic expansion and
contractions of the blastocyst, an increase of the pressure inside the blastocyst itself occurs, the hole
expands and finally the blastocyst can emerge from this rigid envelope.

The inner cell mass will give rise to the pre-embryo,[10] the amnion, yolk sac and allantois, while
the fetal part of the placenta will form from the outer trophoblast layer. The embryo plus its
membranes is called the conceptus, and by this stage the conceptus has reached the uterus.
The zona pellucida ultimately disappears completely, and the now exposed cells of the trophoblast
allow the blastocyst to attach itself to the endometrium, where it will implant. The formation of
the hypoblast and epiblast, which are the two main layers of the bilaminar germ disc, occurs at
the beginning of the second week.[11] Both the embryoblast and the trophoblast will turn into two
sub-layers.[12] The inner cells will turn into the hypoblast layer, which will surround the other
layer, called the epiblast, and these layers will form the embryonic disc that will develop into the
embryo.[11][12] The trophoblast will also develop two sub-layers: the cytotrophoblast, which is in
front of the syncytiotrophoblast, which in turn lies within the endometrium.[11] Next, another
layer called the exocoelomic membrane or Heuser's membrane will appear and surround the
cytotrophoblast, as well as the primitive yolk sac.[12] The syncytiotrophoblast will grow and will
enter a phase called lacunar stage, in which some vacuoles will appear and be filled by blood in
the following days.[11][12] The development of the yolk sac starts with the hypoblastic flat cells that
form the exocoelomic membrane, which will coat the inner part of the cytotrophoblast to form the
primitive yolk sac. An erosion of the endothelial lining of the maternal capillaries by the
syncytiotrophoblastic cells results in the formation of the maternal sinusoids from where the
blood will begin to penetrate and flow into and through the trophoblastic lacunae to give rise to
the uteroplacental circulation.[13][14] Subsequently, new cells derived from yolk sac will be
established between trophoblast and exocoelomic membrane and will give rise to extra-embryonic
mesoderm, which will form the chorionic cavity.[12]

At the end of the second week of development, some cells of the trophoblast penetrate and form
rounded columns into the syncytiotrophoblast. These columns are known as primary villi. At the
same time, other migrating cells form into the exocoelomic cavity a new cavity named the secondary
or definitive yolk sac, smaller than the primitive yolk sac. [12][13]

Implantation
Trophoblast differentiation

After ovulation, the endometrial lining becomes transformed into a secretory lining in preparation
of accepting the embryo. It becomes thickened, with its secretory glands becoming elongated, and
is increasingly vascular. This lining of the uterine cavity (or womb) is now known as the decidua,
and it produces a great number of large decidual cells in its increased interglandular tissue. The
blastomeres in the blastocyst are arranged into an outer layer called the trophoblast. The
trophoblast then differentiates into an inner layer, the cytotrophoblast, and an outer layer, the
syncytiotrophoblast. The cytotrophoblast contains cuboidal epithelial cells and is the source of
dividing cells, and the syncytiotrophoblast is a syncytial layer without cell boundaries.

The syncytiotrophoblast implants the blastocyst in the decidual epithelium by projections of

chorionic villi, forming the embryonic part of the placenta. The placenta develops once the
blastocyst is implanted, connecting the embryo to the uterine wall. The decidua here is termed the
decidua basalis; it lies between the blastocyst and the myometrium and forms the maternal part of
the placenta. The implantation is assisted by hydrolytic enzymes that erode the epithelium. The
syncytiotrophoblast also produces human chorionic gonadotropin, a hormone that stimulates the
release of progesterone from the corpus luteum. Progesterone enriches the uterus with a thick lining
of blood vessels and capillaries so that it can oxygenate and sustain the developing embryo. The
uterus liberates sugar from stored glycogen from its cells to nourish the embryo.[15] The villi begin
to branch and contain blood vessels of the embryo. Other villi, called terminal or free villi, exchange
nutrients. The embryo is joined to the trophoblastic shell by a narrow connecting stalk that
develops into the umbilical cord to attach the placenta to the embryo. [12][16] Arteries in the decidua
are remodelled to increase the maternal blood flow into the intervillous spaces of the placenta,
allowing gas exchange and the transfer of nutrients to the embryo. Waste products from the embryo
will diffuse across the placenta.
As the syncytiotrophoblast starts to penetrate the uterine wall, the inner cell mass (embryoblast)
also develops. The inner cell mass is the source of embryonic stem cells, which are pluripotent and
can develop into any one of the three germ layer cells, and which have the potency to give rise to all
the tissues and organs.

Embryonic disc

The embryoblast forms an embryonic disc, which is a bilaminar disc of two layers, an upper layer
called the epiblast (primitive ectoderm) and a lower layer called the hypoblast (primitive
endoderm). The disc is stretched between what will become the amniotic cavity and the yolk sac.
The epiblast is adjacent to the trophoblast and made of columnar cells; the hypoblast is closest to
the blastocyst cavity and made of cuboidal cells. The epiblast migrates away from the trophoblast
downwards, forming the amniotic cavity, the lining of which is formed from amnioblasts developed
from the epiblast. The hypoblast is pushed down and forms the yolk sac (exocoelomic cavity) lining.
Some hypoblast cells migrate along the inner cytotrophoblast lining of the blastocoel, secreting an
extracellular matrix along the way. These hypoblast cells and extracellular matrix are called
Heuser's membrane (or the exocoelomic membrane), and they cover the blastocoel to form the yolk
sac (or exocoelomic cavity). Cells of the hypoblast migrate along the outer edges of this reticulum
and form the extraembryonic mesoderm; this disrupts the extraembryonic reticulum. Soon pockets
form in the reticulum, which ultimately coalesce to form the chorionic cavity (extraembryonic
coelom).

Gastrulation

Histogenesis of the three germ layers

Development of organs and organ systems

Nine-week-old human embryo from an ectopic pregnancy

Organogenesis is the development of the organs that begins during the third to eighth week, and
continues until birth. Sometimes full development, as in the lungs, continues after birth. Different
organs take part in the development of the many organ systems of the body.

Blood

Haematopoietic stem cells that give rise to all the blood cells develop from the mesoderm. The
development of blood formation takes place in clusters of blood cells, known as blood islands, in
the yolk sac. Blood islands develop outside the embryo, on the umbilical vesicle, allantois,
connecting stalk, and chorion, from mesodermal hemangioblasts.

In the centre of a blood island, hemangioblasts form the haematopoietic stem cells that are the
precursor to all types of blood cell. In the periphery of a blood island the hemangioblasts
differentiate into angioblasts, the precursors to the blood vessels. [21]

Heart and circulatory system

The heart is the first functional organ to develop and starts to beat and pump blood at around 22
days.[22] Cardiac myoblasts and blood islands in the splanchnopleuric mesenchyme on each side of
the neural plate, give rise to the cardiogenic region.[12]: 165 This is a horseshoe-shaped area near to
the head of the embryo. By day 19, following cell signalling, two strands begin to form as tubes in
this region, as a lumen develops within them. These two endocardial tubes grow and by day 21 have
migrated towards each other and fused to form a single primitive heart tube, the tubular heart. This
is enabled by the folding of the embryo which pushes the tubes into the thoracic cavity.[23]
Digestive system

The digestive system starts to develop from the third week and by the twelfth week, the organs
have correctly positioned themselves.

Respiratory system

The respiratory system develops from the lung bud, which appears in the ventral wall of the
foregut about four weeks into development. The lung bud forms the trachea and two lateral
growths known as the bronchial buds, which enlarge at the beginning of the fifth week to form
the left and right main bronchi. These bronchi in turn form secondary (lobar) bronchi; three on
the right and two on the left (reflecting the number of lung lobes). Tertiary bronchi form from
secondary bronchi.

While the internal lining of the larynx originates from the lung bud, its cartilages and muscles
originate from the fourth and sixth pharyngeal arches.[24]

Urinary system

Kidneys

Three different kidney systems form in the developing embryo: the pronephros, the mesonephros
and the metanephros. Only the metanephros develops into the permanent kidney. All three are
derived from the intermediate mesoderm.
Pronephros

The pronephros derives from the intermediate mesoderm in the cervical region. It is not
functional and degenerates before the end of the fourth week.

Mesonephros

The mesonephros derives from intermediate mesoderm in the upper thoracic to upper lumbar
segments. Excretory tubules are formed and enter the mesonephric duct, which ends in the
cloaca. The mesonephric duct atrophies in females, but participate in development of the
reproductive system in males.

Metanephros

The metanephros appears in the fifth week of development. An outgrowth of the mesonephric
duct, the ureteric bud, penetrates metanephric tissue to form the primitive renal pelvis, renal
calyces and renal pyramids. The ureter is also formed.

Bladder and urethra

Between the fourth and seventh weeks of development, the urorectal septum divides the cloaca into
the urogenital sinus and the anal canal. The upper part of the urogenital sinus forms the bladder,
while the lower part forms the urethra.[24]

Reproductive system Integumentary

system

The superficial layer of the skin, the epidermis, is derived from the ectoderm. The deeper layer,
the dermis, is derived from mesenchyme.

The formation of the epidermis begins in the second month of development and it acquires its
definitive arrangement at the end of the fourth month. The ectoderm divides to form a flat layer of
cells on the surface known as the periderm. Further division forms the individual layers of the
epidermis.

The mesenchyme that will form the dermis is derived from three sources:

The mesenchyme that forms the dermis in the limbs and body wall derives from the lateral
plate mesoderm
 The mesenchyme that forms the dermis in the back derives from paraxial mesoderm

The mesenchyme that forms the dermis in the face and neck derives from neural crest cells[24]

Nervous system

Development of brain in eight-week-old embryo

Late in the fourth week, the superior part of the neural tube bends ventrally as the cephalic flexure
at the level of the future midbrain—the mesencephalon. Above the mesencephalon is the
prosencephalon (future forebrain) and beneath it is the rhombencephalon (future hindbrain).

Cranial neural crest cells migrate to the pharyngeal arches as neural stem cells, where they
develop in the process of neurogenesis into neurons.

The optical vesicle (which eventually becomes the optic nerve, retina and iris) forms at the basal
plate of the prosencephalon. The alar plate of the prosencephalon expands to form the cerebral
hemispheres (the telencephalon) whilst its basal plate becomes the diencephalon. Finally, the optic
vesicle grows to form an optic outgrowth.

Development of physical features

Face and neck

Limbs
Ears
Eyes