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Aims

  1. Understanding of germ layer contributions to the early gastrointestinal tract (GIT)
  2. Understanding of the folding of the GIT
  3. Understanding of three main GIT embryonic divisions
  4. Understanding of associated organ development (liver, pancreas, spleen)
  5. Brief understanding of mechanical changes (rotations) during GIT development
  6. Brief understanding of gastrointestinal abnormalities

Sources

  • Look at the notes from Larsen's [1]
  • Click here for Mark Hill's site for this lecture.

Introduction

The developing GIT
  • The heart was one of the organs that began to form in week 4. Along with it, so does the GIT.
  • The GIT is one of those parts of the body that doesn't function before birth.
  • The GIT is formed from all three of the germ cell layers (endoderm, mesoderm, ectoderm).
  • The GIT folds mechanically in several different ways, three dimensionally
  • There are three main divisions of the gut: foregut, midgut and hindgut
  • We may also talk about the spleen (even though it's not a GIT organ), because both the spleen and midgut develop together in the dorsal mesentery
  • The textbooks linked on his website take you to the full text of these books

Week 3

Gastrulation and neurulation

  • The major process we're concerned with in week 3 is gastrulation (beginning of week 3) - the migration of epiblast cells through the primitive streak of our initially bilaminar embryo, to form a trilaminar embryo. This forms the germ layers (endoderm, mesoderm, ectoderm). The primitive streak forms in the caudal epiblast (near the end of the embryonic disc which is currently bilaminar). Rostrally, the primitive streak is expanded as the primitive node, which contains a circular indentation (the primitive pit), continuous with the primitive groove. The migrated cells form the endoderm, and the intraembryonic mesoderm. The cells which didn't migrate form the ectoderm. Also in week 3 are the formation of the notochord, paraxial mesoderm (forming the head mesoderm in the rostral area and somites everywhere else), intermediate mesoderm (urogenital tract) and lateral plate mesoderm (body wall and GIT). Neural induction (neurulation) occurs, with the formation of a neural plate that folds into a neural tube. Neural crest cells from the lateral edges of the neural plate form, and will migrate to form various neural structures in the embryo. The endoderm folds to form the foregut, midgut and hindgut. The prechordal plate is a thickening of the cranial midline endoderm, cranial to the tip of the extending notochord - this makes the oropharyngeal membrane and also contributes the cardiogenic mesoderm for heart formation[2]
  • Superior surface = ectoderm (nervous system and epithelium)
  • Inferior surface = endoderm (forms the lining of the gut)
  • Components of the trilaminar embryo and their contributions to the GIT:
    1. Endoderm - epithelium and associated glands, organs
    2. Mesoderm (splanchnic) - mesentery, CT, smooth muscle, blood vessels, organs
    3. Ectoderm (neural crest) - enteric nervous system
  • Rostral end = buccopharyngeal membrane
  • Caudal end = cloacal membrane
    • These two membranes at the ends of the embryo are endoderm and ectoderm meeting together (no mesoderm present in these areas). They also define the upper and lower ends of the GIT
Folding of the GIT and narrowing at the cloacal and buccopharyngeal membranes
  • There is a folding of the flat disc ventrally, converting the flat endodermal layer into a tube-like structure. This extends into a closed diverticulum at the foregut ending in the buccopharyngeal membrane and similarly at the hindgut forming the cloacal membrane. This closure doesn't occur in the midgut, which is continuous with the yolk sac. The connection between the midgut and the yolk sac is called the yolk stalk or the vitelline duct. The endoderm of the gut is continuous with that of the yolk sac. Surrounding the endoderm will be the mesoderm.
  • The endoderm forms a hollow tube, and the mesoderm surrounds this area, and the neural tube is dorsally to that
  • 3rd week we form the 3 major body cavities: pericardial, pleural and peritoneal cavities
  • See his diagram schematic of the development of the layers
  • Splanchnic mesoderm is associated with the gut tube. This forms from the lateral plate, and a cavity forms in the lateral plate mesoderm (horseshoe shaped mesoderm). The upper part of the cavity will be the pericardial cavity and the lower bit will be peritoneal cavity. The two arms will be the pleural cavity.
  • Foregut extends up behind the heart tube and opens at the buccopharyngeal membrane
  • A second pocketing of the endoderm is below the yolk stalk (of the umbilical cord) - this is the allantois (most important in reptiles and birds, it's important in waste storage, but in humans it is a vestige)

Folding

  • Folding of the embryonic disc then occurs ventrally around the notochord (a rod-like region of mesoderm running rostro-caudally in the midline).
  • Planes of folding (in relation to the notochord):
    • Laterally (either side of the notochord) lies paraxial mesoderm.
    • Rostrally (above the notochord end) lies the buccopharyngeal membrane (see below), above this again is the mesoderm region forming the heart.
    • Caudally (below the notochord end) lies the primitive streak (where gastrulation occurred), below this again is the cloacal membrane (see below).
    • Dorsally (above the notochord) lies the neural tube then ectoderm.
    • Ventrally (beneath the notochord) lies the mesoderm then endoderm.

Week 4

Intraembryonic coelom

Week 4 (Carnegie stage 11)
  • The lateral plate mesoderm splits to form a horseshoe-shaped structure, the dorsal portion of which is the somatic mesoderm and the ventral portion of which is the splanchnic mesoderm.
  • 4th week onwards - there is a narrowing of the yolk stalk, and the yolk sac becomes associated with the wall of the conceptus, and becomes a vestige (remnant). The amnion grows.
  • There is a mesodermal attachment of the midgut to the posterior part of the peritoneal cavity (the dorsal mesentery) - this becomes the source of vascularisation of the midgut and also supports the portal circulation.
  • 4th-5th week of development: the buccopharyngeal membrane begins to degenerate (the first pharyngeal arch forms in this time). This allows amniotic fluid to enter the GIT and the respiratory tract. The amniotic fluid fills the GIT through all of the remainder of development. The indentation on the front of the head is the stomadeum. The floor of this structure is made up of the buccopharyngeal membrane.
  • Pharynx - we get expansions: the pharyngeal arches
  • In the neck area - we get a lung diverticulum (starting to form the respiratory tract)
  • Beneath this area we get a slight expansion in the gut tube (the stomach) in all directions, with a larger prominence in front of it (the liver - central station for all of the arteries and veins of the foetus). There is also a cystic diverticulum for the gallbladder.

The stomach

  • The development of the stomach occurs as a rapid expansion of the gut tube in all directions to make a fusiform shape (in the 4th week).
  • First 90 degree rotation of the stomach:The posterior wall of the stomach grows much faster than the anterior wall, producing a bending of the tube ventrally, forming a J-shaped structure. This forms the greater curvature of the stomach on the posterior wall and the lesser curvature of the stomach on the anterior wall
  • Second 90 degree rotation of the stomach in development is the rapid growth of the mesentery supporting the stomach, causing the stomach to rotate laterally, and bringing it into the anatomical position.
    • This later phase establishes the small cavity that forms behind the stomach (the lesser sac)
  • In the dorsal mesentery, at about the level of the stomach, we get the formation of the spleen (not a GIT organ)
  • At this stage, the respiratory diverticulum has branched to form the two main bronchi
  • Note that the lateral rotation of the stomach shifts the liver to its anatomical location (pointing in the mediolateral axis across the body)
  • The stomach runs into the duodenum, which runs outside of the embryo, and then runs back into the embryo in a region called the cloaca

The liver

thumb
  • Liver differentiates at the level of the transverse septum
  • See below for more information

Week 5

Canalization

  • Canalization: the epithelium of the GIT proliferates and blocks the lumen of the GIT. Later on, vacuoles or spaces form in the solid lumen, to eventually form a hollow lumen later on.
    • There can be abnormalities: if the vacuolation doesn't open up the entire lumen, you end up with a duplicated tube (by a septum) or a narrowing/stenosis at some point. Possible abnormalities: atresia, stenosis or duplications.
  • The epithelium begins to differentiate and form the glands that we recognise in the gut
  • Sequence of events:
  1. The endodermal epithelial wall proliferates
  2. The early tract lumen is transiently lost (occluded) (week 6)
  3. Vacuolated spaces form (week 7-8)
  4. The gut tube is completely recanalised (lumen is free again - week 9)
  5. Epithelium differentiates and forms the glands and specific epithelium we recognise in the adult gut.

Mesentery development

The folded dorsal mesogastrium fuses to form the greater omentum, an apron-like structure that flops in front of the intestines.

Diagram = stomach cut laterally.

  • Ventral mesentery forms falciform ligament of the liver and lesser omentum. The dorsal mesogastrium at the level of the stomach forms the greater omentum of the stomach, once its two folds fuse together, which occurs in the foetal period.
    • Continues to grow and extend down into the peritoneal cavity, eventually lying anterior to the small intestines
    • This fold of mesentery fuses to form a single sheet
  • The dorsal mesentery is the true mesentery of the gut (containing vasculature for the the gut). Some organs become retroperitoneal (fused to the body wall).

See his animations - they're actually quite good.

  • Foregut = pharynx down to superior part of the duodenum
  • Midgut = inferior part of the duodenum downwards.
  • At the level of the liver, there several diverticula:
    • Hepatic diverticulum - liver
    • Cystic diverticulum - gallbladder
    • Ventral pancreatic diverticulum
    • Dorsal pancreatic diverticulum

Spleen

  • Mesoderm within the dorsal mesogastrium (week 5) forms a long strip of cells adjacent to the forming stomach above the developing pancreas
  • Vascular and immune organ, no direct GIT function

Week 8-10

Intestine herniation and rotation

Week 10 foetus

The midgut grows in length as a loop extending ventrally, returning as the hindgut

  • The midgut is connected by a dorsal mesentery
  • The midgut rotates to form the adult anatomical position
  • Midgut lies outside the body wall (herniation).
  • This herniation allows a growth in the length of the midgut, and also allows rotation of the midgut to form its anatomical shape. We don't see it return to the body wall until about the 11th week (the body becomes large enough to contain it, and engulfs the midgut).
  • Abnormalities: gastroschisis, omphalocele
  • The rotation of the herniated midgut occurs in a series of rotational procedures. We're not expected to remember these rotations.
  • The green circle represents the hole in the body wall out of which the midgut is herniated
  • Rotation: think of the superior mesenteric artery as the axis of rotation (if these rotations don't occurs around SMA, then this artery gets occluded, killing the gut it supplies).
  • Neural crest cells migrate into the wall, forming the enteric nervous system, responsible for peristalsis and secretion

Hindgut

Degenerating buccopharyngeal membrane, developing the oral cavity
  • The caudal end of the gut tube is hindgut - it was originally a large open space (common to the urinary, genital and GIT systems - the cloaca).
  • In the hindgut, there is a septation - the mesoderm in the superior end of the cloacal space grows downwards. This splits the cloaca into two halves: the ventral half (the urogenital part of the cloaca) and a dorsal part (the rectal part of the cloaca).
    • These are respectively called the superior Tourneux fold and the lateral Rathke fold.
  • Eventually the septum fuses with the cloacal membrane (which then breaks down after fusion of the septum with the cloacal membrane).

Analogy between septations of the hindgut and the foregut:

  • In the foregut, the stomadeum was the indentation of ectoderm, which fuses to form the oral cavity, then the buccopharyngeal membrane degenerates to form the oral cavity
  • Similarly, in the cloaca, a mesodermal septum fuses with the cloacal membrane to form the anal cavity.

Therefore:

  • The anus is ectodermal in origin
  • The rectum is mesodermal in origin

NB:

  • Hindgut - distal third transverse colon, descending and sigmoid colon, rectum
  • Anal pit - distal third of anorectal canal (ectodermal)

Divisions of the gut tube

Vascular divisions of the developing GIT

During the 4th week the 3 distinct portions (fore-, mid- and hind-gut) extend the length of the embryo and will contribute different components of the GIT. These 3 divisions are also later defined by their vascular (artery) supply.

  • The arteries supplying the GIT (CA, SMA, IMA) come off the dorsal aorta (which fused from a pair of aortae)
  • Superior branch of the aorta is the celiac artery which supplies the foregut
  • The middle branch of the aorta is the superior mesenteric artery which supplies the midgut
  • The hindgut is supplied by a branch beneath this called the inferior mesenteric artery
  • These three arteries define the three divisions of our GIT
  • The lining epithelium and glands of the gut is endoderm, then there is splanchnic mesoderm surrounding it (CT and bilaminar smooth muscle throughout the wall of the GIT, and the stroma of the liver and pancreas). Then there is a cavity.
    • Endoderm also contributes the pancreas, spleen and liver
    • Ectoderm forms part of the oral cavity and also the anus. Another ectodermal contribution to the GIT is from the neural crest (on the posterior surface of the neural tube, and these cells migrated out into the splanchnic mesoderm, to form the adrenal medulla and the sympathetic ganglia). The enteric nervous system of the gut (ganglia embedded within the two layers of smooth muscle and the neural supply to the gut) is ectodermal in origin. This is necessary for peristalsis. An abnormality in the formation of GIT ganglia stops the baby passing stools.
  1. Foregut - celiac artery (Adult: pharynx, esophagus, stomach, upper duodenum, respiratory tract, liver, gallbladder pancreas)
  2. Midgut - superior mesenteric artery (Adult: lower duodenum, jejunum, ileum, cecum, appendix, ascending colon, half transverse colon)
  3. Hindgut - inferior mesenteric artery (Adult: half transverse colon, descending colon, rectum, superior part anal canal)

Foetal growth of the small intestine and liver

  • During the foetal period of development, the intestine grows in a linear (constant growth) fashion until 25 weeks when it is 1400mm long.
  • The liver starts out very low in mass (12 weeks), and there is a large growth in liver mass from week 30 onwards (making more of the same components).

Liver

Week 4: an early human digestive tube. The liver forms as buds from the midgut just caudal to the fusiform expansion of the GIT for the stomach
Week 4: a later human digestive tube, showing many of the features discussed here.
  • Forms from a series of buds, describes as the hepatic buds (hepatic diverticula). It forms at the level of the transverse septum.
  • There are two major buds: the left bud (form the left, quadrate and caudate lobes) and the right bud (forms the right lobe).
  • The liver's major role in the embryo is in haematopoeisis (this is before we have bone marrow)
  • Differentiates to form the hepatic diverticulum and hepatic primordium, generates the gall bladder then divides into right and left hepatic (liver) buds.
  • Hepatic Buds - form hepatocytes, produce bile from week 13 (forms meconium of newborn)
    • Left Hepatic Bud - left lobe, quadrate, caudate (both q and c anatomically Left) caudate lobe of human liver consists of 3 anatomical parts: Spiegel's lobe, caudate process, and paracaval portion.
    • Right Hepatic Bud - right lobe
  • Bile duct - 3 connecting stalks (cystic duct, hepatic ducts) which fuse.
  • Early liver also involved in blood formation, after the yolk sac and blood islands acting as a primary site.

Pancreas

The pancreas rotates with the stomach to become a retroperitoneal structure
Week 8 pancreas
  • Forms beneath the level of the liver - as a ventral bud (usually singular, sometimes double) and a larger dorsal bud
  • The ventral bud of the pancreas rotates around and fuses with the dorsal bud (due to the rotation of the stomach).
  • This development of the pancreas can lead to a variety of ways the pancreas drains into the duodenum (there is a huge variation).
  • If these branches don't get fused together properly in stomach folding, then the ventral bud can fuse around the duodenum to form an annular pancreas.
  • The endoderm will form all of the duct system. It's thought that the endoderm also contributes to the pancreatic islets (the endocrine pancreas-insulin etc, which is embedded in the exocrine pancreas)
  • The pancreas rotates around and is fused into the posterior body wall (becomes secondarily retroperitoneal)
    • Similarly the ascending and descending colon and the duodenum are also retroperitoneal structures

Further notes:

  • Pancreatic buds - endoderm, covered in splanchnic mesoderm
  • Pancreatic bud formation – duodenal level endoderm, splanchnic mesoderm forms dorsal and ventral mesentery, dorsal bud (larger, first), ventral bud (smaller, later)
  • Duodenum growth/rotation – brings ventral and dorsal buds together, fusion of buds, exocrine function
  • Pancreatic duct – ventral bud duct and distal part of dorsal bud
  • Pancreatic islets - endocrine function (week 10 onwards)

Spleen

  • Mesoderm within the dorsal mesogastrium form a long strip of cells adjacent to the forming stomach above the developing pancreas.
  • The spleen is located on the left side of the abdomen and has a role initially in blood and then immune system development.
  • The spleen's haematopoietic function (blood cell formation) is lost with embryo development and lymphoid precursor cells migrate into the developing organ.
  • Vascularization of the spleen arises initially by branches from the dorsal aorta.

Abnormalities

  • Atresia - complete blockage of the lumen of the tube (at various levels - oesophageal, duodenal, extrahepatic biliary, anorectal)
  • Stenosis - narrowing of the lumen (duodenal or pyloric)
  • Duplication - incomplete recanalisation resulting in parallel lumens, this is really a specialised form of stenosis

Meckel's diverticulum

Meckel's diverticulum
  • Very common abnormality - improper closure and absorption of the vitelline duct during early development
  • This occurs if the yolk stalk doesn't completely degenerate - it forms a small pocket on the midgut (like the appendix). It can lead to abnormalities in gut rotation.
    • Yolk stalk (vitelline duct or omphalomesenteric duct) is a transient developmental duct that connects the yolk to the primitive GIT

Intestinal malrotation

  • Bands of CT attached to the gut tube can lead to malrotation of the intestine.
  • Presents clinically in symptomatic malrotation as:
    • Neonates - bilious vomiting and bloody stools
    • Newborn - bilious vomiting and failure to thrive
    • Infants - recurrent abdominal paint, intestinal obstruction, malabsorption/diarrhoea, peritonitis/septic shock, solid food intolerance, common bile duct obstruction, abdominal distention and failure to thrive
  • Ladd's bands - a series of bands crossing the duodenum which can cause duodenal obstruction

Aganglionic colon

Intestinal aganglionosis (aganglionic colon)
  • AKA megacolon or Hirschsprung's Disease - material accumulates in the gut due to lack of peristalsis and causes it to swell
  • Occurs if the neural crest cells don't migrate correctly into the gut - stopping peristalsis from occurring
  • Treatment: resect that region of gut. If the region is too large, we have to set up a stoma.

Gastroschisis

  • (aka omphalocele, paraomphalocele, laparoschisis, abdominoschisis, abdominal hernia)
  • Abnormality of the body wall, causing herniation of foetal abdominal viscera (intestines and/or organs) into the amniotic cavity
  • Incidence: 1.66/10,000, occurring more frequently in young mothers (less than 20 years old).
  • By definition, it is a body wall defect, not a gastrointestinal tract defect, which in turn impacts upon GIT development
  • This indirect developmental effect (one system impacting upon another) occurs in several other systems
  • The gut isn't externalised correctly
  • Omphalocele - appears similar to gastroschisis, herniation of the bowel, liver and other organs into the intact umbilical cord, the tissues being covered by membranes unless the latter are ruptured.

References

  1. Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone.
  2. Schoenwolf, G. C., Bleyl, S. B., Brauer, P. ., & Francis-West, P. . (2009). Larsen’s Human Embryology (4th ed.). New York: Churchill Livingstone.