Gastrointestinal Tract - Liver Development

Embryology - 16 Apr 2024        Expand to Translate
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Introduction

Embryonic hepatic bud formation.

This section of notes gives an overview of how the liver develops. The transverse septum (septum transversum) arises at an embryonic junctional site. The junctional region externally is where the ectoderm of the amnion meets the endoderm of the yolk sac. The junctional region internally is where the foregut meets the midgut. The mesenchymal structure of the transverse septum provides a support within which both blood vessels and the liver begin to form. Arises at embryonic junction (septum transversum): externally is where ectoderm of amnion meets endoderm of yolk sac and internally is where the foregut meets the midgut. Mesenchymal structure of transverse septum provides a support within which both blood vessels and liver begin to form in the underlying splanchnic mesoderm.

In the early embryo, the liver and heart grow rapidly forming obvious external swellings on the ventral embryo surface. The liver's initial embryonic function is mainly cardiovascular. Firstly, as a vascular connection between the developing placental vessels to the heart. Secondly, as a haemopoietic tissue where blood stem cells reside before bone marrow development.

See also Liver Histology showing both developmental and adult histology.

Historic Embryology:1912 Liver

Some Recent Findings

Human Liver (week 8, GA week 10)

Three-dimensional reconstructions of intrahepatic bile duct tubulogenesis in human liver "Samples from human prenatal livers ranging from 7 weeks + 2 days to 15½ weeks post conception as well as adult normal and acetaminophen intoxicated liver were used. ....In the developing human liver, three-dimensional reconstructions using multiple marker proteins confirmed that the human intrahepatic biliary tree forms through several developmental stages involving an initial transition of primitive hepatocytes into cholangiocytes shaping the ductal plate followed by a process of maturation and remodeling where the intrahepatic biliary tree develops through an asymmetrical form of cholangiocyte tubulogenesis. Dynamic signaling network for the specification of embryonic pancreas and liver progenitors Studies of the formation of pancreas and liver progenitors have focused on individual inductive signals and cellular responses. Here, we investigated how bone morphogenetic protein, transforming growth factor-beta (TGFbeta), and fibroblast growth factor signaling pathways converge on the earliest genes that elicit pancreas and liver induction in mouse embryos. The inductive network was found to be dynamic; it changed within hours. Different signals functioned in parallel to induce different early genes, and two permutations of signals induced liver progenitor domains, which revealed flexibility in cell programming. Also, the specification of pancreas and liver progenitors was restricted by the TGFbeta pathway." Notch signaling controls liver development by regulating biliary differentiationIn the mammalian liver, bile is transported to the intestine through an intricate network of bile ducts. Notch signaling is required for normal duct formation, but its mode of action has been unclear. Here, we show in mice that bile ducts arise through a novel mechanism of tubulogenesis involving sequential radial differentiation. Notch signaling is activated in a subset of liver progenitor cells fated to become ductal cells, and pathway activation is necessary for biliary fate."

More recent papers

This table allows an automated computer search of the external PubMed database using the listed "Search term" text link. This search now requires a manual link as the original PubMed extension has been disabled. The displayed list of references do not reflect any editorial selection of material based on content or relevance. References also appear on this list based upon the date of the actual page viewing. References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability. More? References | Discussion Page | Journal Searches | 2019 References | 2020 References Search term: Liver Embryology <pubmed limit=5>Liver Embryology</pubmed>

Movies

‎‎Lesser sac Page | Play

‎‎Greater Omentum Page | Play

Liver Development Stages

Human Liver Growth (weight grams)

Carnegie Stage	Feature
11	hepatic diverticulum development
12	cell differentiation septum transversum forming liver stroma hepatic diverticulum forming hepatic trabeculae
13	epithelial cord proliferation enmeshing stromal capillaries
14	hepatic gland and its vascular channels enlarge hematopoietic function appeared
18	obturation due to epithelial proliferation bile ducts became reorganized (continuity between liver cells and gut)
18 to 23	biliary ductules developed in periportal connective tissue produces ductal plates that receive biliary capillaries
Human data from Godlewski G, etal, see also liver development in the rat during the embryonic period (Carnegie stages 15-23). (More? Timeline human development)

Embryonic Liver Development Timeline  

Carnegie Stage	Age (days)	CRL (mm)	Biliary system	Vascular	Hepatic parenchyma
14	33	7	Bile duct - primordial duct links primitive intestine and liver parenchyma. Thick-walled tube (95 µm diameter) small lumen (22 µm diameter). Gall bladder - elongated tube further dilated, thick wall (125 µm diameter) and a narrow lumen (43 µm diameter).	Hepatic sinusoids - intra-hepatic vasculature present Three venous tributaries flow into the liver sinusoids - right and left placental vein and a single vitelline vein.	Cords of liver cells fragmented by vascular network of hepatic sinusoids. Between pericardial cavity (top) and mesonephros (bottom). Upper pole of the liver lies close to the septum transversum and early ventricles. Liver occupies the majority of abdominal cavity.
18	46	15	Bile duct (future common bile duct), and a common hepatic duct, in contact with liver parenchyma without penetration. Primordium of accessory bile tract is an elongated and fusiform gall bladder projecting forward and by a short cystic duct that opens into common bile duct. Bile duct empties into second part of duodenum on its posterior side.	Portal system visible - portal vein (100 µm diameter) arises from connection of upper mesenteric vein then at region of hepatic hilum (285 µm) divides into portal branches. Left umbilical vein empties into anterior extremity of the left portal branch. Ductus venosus (80 µm) connects the initial portion of left portal vein to the inferior vena cava. Hepatic venous system 3 branches - left hepatic vein (120 µm in diameter), middle hepatic vein (220 􏰁µm in diameter) and right hepatic vein (160 µm in diameter). Flows into the sub-cardinal vein.	Liver parenchyma has two anatomical lobes (right and left lobe), separated by anteroposterior plane formed by placental vein.
21	53	22.5	Bile duct morphology as earlier stage. Common bile duct empties at the level of the proximal duodenum.	Portal vein arises from joining of splenic vein and superior mesenteric vein. At the level of the hepatic hilum, portal vein divides into two branches, right portal branch (420 µm in diameter) and left portal branch (540 µm in diameter). Right portal branch gives rise to a thin branch to caudate lobe. Ventral branch gives rise to segmental portal veins (VIII and V). Dorsal branch gives rise to the segmental portal veins (VI and VII). Ductus venosus connects initial portion of left portal vein to inferior vena cava, just upstream from hepatic vein afferents. Hepatic venous system as for previous stage.	Hepatic parenchyma a large rounded mass.
23	58	27	Bile duct morphology as earlier stage.	Portal venous system complete. Ductus venosus (40 µm) connects initial portion of portal vein to middle hepatic vein. hepatic venous system has changed very little from the previous stage. Three hepatic veins empty into inferior vena cava.	Liver parenchyma roughly oval shape, 2 symmetrical hepatic lobes. The quadrate and caudate lobes are identifiable. Upper pole of the liver bounded above by diaphragm.
Data from a recent human study Links: liver | Carnegie stage 14 | 18 | 21 | 23 | simple embryonic timeline | Timeline human development

Liver Buds

• Differentiates to form the hepatic diverticulum and hepatic primordium, generates the gall bladder then divides into right and left hepatic (liver) buds.
• Three connecting stalks (cystic duct, hepatic ducts) which fuse to form bile duct.

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

Liver Structural Origins

The Liver Lobule

• Hepatic Buds - form hepatocytes, produce bile from week 13 (forms meconium of newborn)
• Vitelline Veins - form sinusoids
• Mesenchyme - form connective tissue and Kupffer cells

Function - Haemopoiesis

Embryonic liver also involved in blood formation, after the yolk sac and blood islands acting as a primary site.

Components of Liver Formation

Mouse liver development signaling.

Primitive Endoderm

foregut diverticulum

foregut-midgut junction septum transversum hepatic diverticulum cystic primordium gall bladder common bile duct hepatic ducts liver/gall bladder hepatic primordium hepatic parenchyma hepatic sinusoids lobes of liver liver/gall bladder

midgut region hindgut diverticulum (pocket)

Data from mouse

Hepatoblasts - endoderm-derived cells can differentiate into either:

1. hepatocytes - populate the bulk of the liver parenchyma.
2. cholangiocytes - line the intrahepatic bile ducts.

Links: Endoderm | Mouse Development

Development

Stage 13

stage 13 embryo

The images below link to larger cross-sections of the mid-embryonic period (end week 4) stage 13 embryo starting just above the level of the liver and then in sequence through the liver to the level of the stomach. Note the relative position of the liver with respect to the abdominal cavity, the gall bladder and the heart.

The transverse septum differentiates to form the hepatic diverticulum and the hepatic primordium, these two structures together will go on to form different components of the mature liver and gall bladder. At this stage large vascular channels can be seen coursing through the liver primordium.

Stage 13 (serial labeled images)

D3L	D4L	D5L	D6L	D7L	E1L
G6L	G7L

Links: Carnegie stage 13 - serial sections | Embryo Serial Sections | Embryo Carnegie stage 13 Movies

Stage 22

Virtual Slide Features - Stage 22 Liver
	Virtual Slide - Stage 22 Liver and Ductus Venosus      All Virtual Slides The links shown in the table below are to specific features shown on the Human embryo (stage 22) Liver and Ductus Venosus virtual slide. See also notes on Liver Development Clicking the text will open the slide at a detailed view with the structure generally located in the centre of the view. The slide then can also be zoomed out from the set magnification using the controls in the upper left or the mouse. Use your browser back button to return to this table.			You can also make your own selected feature view. Set the virtual slide to the region and zoom of interest. Click the Permalink (lower righthand corner). Then bookmark in your browser, or copy the web address. See also Permalink help
Cardiovascular ductus venosus dorsal aorta inferior vena cava	Liver ductus venosus hepatocytes sinusoids	Endocrine R adrenal (fetal cortex) L adrenal (fetal cortex)	Musculoskeletal vertebral body (cartilage) rib (cartilage) body wall (sk. muscle)	Neural spinal cord dorsal root ganglia	Gastrointestinal stomach (pylorus)

The images below link to larger cross-sections of the end of the embryonic period (week 8) stage 22 embryo starting just above the level of the liver and then in sequence through the entire liver. (Note the sections are viewed from below, LR axis is reversed)

The rapidly developing liver also forms a visible surface bulge on the embryo directly under the heart bulge. The liver now occupies the entire ventral body cavity with parts of the gastrointestinal tract and urinary system "embedded" within its structure. Note in this image the large central ductus venosus.

Stage 22L serial labeled images

E3L	E4L	E5L	E6L	E7L
F1L	F2L	F3L	F4L	F5L

Links: Carnegie stage 22 - serial sections | Embryo Serial Sections | Embryo Carnegie stage 22 Movies

Selected Stage 22 Images

	E3 Overview of liver region for selected high power views shown below. Note the position and size of the developing liver spanning the entire abdomen and within the liver the large central ductus venosus.
	E4 Central veins of liver. Radiating appearance of hepatic sinusoids. unlabeled version
	E5 Central vein with endothelial lining, containing nucleated erythrocytes, fetal red blood cells. The fetal liver has an important haemopoietic role. unlabeled version

Week 9

Paraffin-embedded sections of human embryonic liver at 9 weeks (GA 11 weeks).

A - (Stain - Haematoxylin Eosin) B, C - Alpha-Fetoprotein (AFP) D, G - Cytokeratin 18 (CK18) E, H - Cytokeratin 19 (CK19) F, I - Cytokeratin 7 (CK7)

Ductal Plate

The ductal plate is a primitive biliary epithelium which develops in mesenchyme adjacent to portal vein branches (periportal hepatoblasts). During liver development it is extensively reorganised (ductal plate remodelling) within the developing liver to form the intrahepatic bile ducts (IHBD). If remodelling does not occur, leading to excess of embryonic bile duct structures in the portal tract, these developmental abnormalities are described as "ductal plate malformation" (DPM).

Ductal Plate Malformations

• Interlobular bile ducts - autosomal recessive polycystic kidney disease
• Smaller interlobular ducts - von Meyenburg complexes
• Larger intrahepatic bile ducts - Caroli's disease

Bile Secretion

The epithelial cells that line the bile ducts are called cholangiocytes.

The pathway below describes the production and passage of bile for final excretion into the duodenum:

1. hepatocytes produce bile
2. secreted into bile canaliculi
3. connected to intrahepatic bile ducts
4. intrahepatic bile ducts connect to the hepatic duct
5. then the cystic duct for storage in the gallbladder
6. then the common bile duct into the duodenum

The term extrahepatic bile ducts (EHBDs) is used to describe the hepatic, cystic, and common bile ducts.

The developing bile ducts express VEGF while hepatoblasts express angiopoietin-1, these two signals are thought to regulate arterial vasculogenesis and remodeling of the hepatic artery respectively.

Liver Blood Flow

Dual blood supply of the liver merges upon entry into the liver lobule at the portal field.

1. branches of the portal vein
2. branches of the hepatic artery

The blood flows along the sinusoid and exits at the central vein.

Hepatocytes

Adult Liver sinusoid structure

These are the adult functional cells forming the majority of the liver (80% of the cells).

Many different functions including:

• Storage of substances including glucose (as glycogen), vitamin A (possibly in specialized adipocytes), vitamin B12, folic acid and iron.
• Lipid Turnover synthesis of plasmalipoproteins
• Plasma Protein Synthesis albumin, alpha and beta globulins, prothrombin, fibrinogen
• Metabolism fat soluble compounds (drugs, insecticides), steroid hormones turnover
• Secretion bile (about 1 litre/day)

Kupffer Cells

Kupffer Cells are a population of tissue macrophages found in the lumen of hepatic sinusoids, their role is endocytic against blood-borne materials entering the liver.

Primordial (primitive) macrophages arise in the yolk sac and then differentiate into fetal macrophages, either of these enter the blood and migrate into the developing liver.

Kupffer Cells image

Search PubMed: Kupffer cell development

Liver Associated Vessels

Liver ventral surface and associated veins (human embryo, 24-25 days, after His.)

ductus venosus - shunts approximately half the umbilical vein blood flow directly to the inferior vena cava. portal vein - carries blood from the gastrointestinal tract and spleen to the liver. left umbilical vein - carries oxygenated blood from the placenta to the embryo/fetus. right umbilical vein - vessel degenerates leaving a single (left) umbilical vein. vena revehens - veins from the sinusoid vessels in the liver to the inferior vena cava, that later develop into the hepatic veins.

Adult Liver Transplants

• About 6,000 liver transplant operations are performed in the United States (http://www.liverfoundation.org/education/info/transplant/)
• About 600–700 in the UK every year (http://www.britishlivertrust.org.uk/home/the-liver/liver-transplantation/a-history-of-liver-transplantation-and-current-statistics.aspx).
• The main limitation on numbers are the availability of donor organs.

Histology

The Liver Lobule

• 

  Histology-fetal liver HEx40

• 

  Histology-fetal liver x100

Adult liver Portal Triad

Links: Liver Histology

Abnormalities

Congenital absence of the portal vein (CAPV) - a rare abnormality where the intestinal and splenic venous drainage bypass the liver and drain directly into the systemic veins through various porto-systemic shunts.

Links: Gastrointestinal Tract - Abnormalities

References

Reviews

<pubmed>21199531</pubmed> <pubmed>20551648</pubmed> <pubmed>20169172</pubmed> <pubmed>20159590</pubmed> <pubmed>20086072</pubmed> <pubmed>18484608</pubmed>

Articles

<pubmed>22371217</pubmed> <pubmed>22105167</pubmed> <pubmed>21708104</pubmed>

Search Pubmed

Search Bookshelf Liver Development

Search Pubmed Now: Liver Development | Embryonic Liver Development

Additional Images

Historic

Mall FP. A Study of the Structural Unit of the Liver (1906) Amer. J. of Anat. 5:227-308.

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  Fig 6 human embryo 2.1 mm

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  Fig 7 human embryo 4.3 mm

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  Fig 8 human embryo 4.3 mm

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  Fig 9 human embryo 4.5 mm

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  Fig 10 human embryo 4.5 mm

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  Fig 11 human embryo 4 mm

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  Fig 12 human embryo 6.6 mm

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  Fig 13 human embryo 5 mm

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  Fig 14 human embryo 5 mm

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  Fig 15 human embryo 7 mm

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  Fig 16 human embryo 7 mm

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  Fig 17 human embryo 7 mm

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  Fig 18 human embryo 9 mm

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  Fig 19 human embryo 9 mm

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  Fig 20 human embryo 9 mm

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  Fig 21 human embryo 11 mm

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  Fig 22 human embryo 11 mm

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  Fig 23 human embryo 11 mm

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  Fig 24 human embryo 11 mm

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  Fig 25 human embryo 11 mm

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  Fig 26 human embryo 20 mm

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  Fig 27 human embryo 20 mm

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  Fig 28 human embryo 24 mm

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  Fig 29 model human embryo 24 mm

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  Fig 30 model human embryo 24 mm

Glossary Links

Glossary: A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | Numbers | Symbols | Term Link

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Cite this page: Hill, M.A. (2024, April 16) Embryology Gastrointestinal Tract - Liver Development. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Gastrointestinal_Tract_-_Liver_Development

What Links Here?

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