Gastrointestinal Tract - Liver Development

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. This structure grows rapidly.

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.

See also Liver Histology showing both developmental and adult histology.

GIT Links: Introduction | Lecture - GIT | Endoderm | Stomach | Liver | Gall Bladder | Pancreas | Intestine | Tongue | Taste | Stage 13 | Stage 22 | Abnormalities | Movies | Postnatal | Milk | Tooth | Tongue | BGD Lecture | BGD Practical | Category:Gastrointestinal Tract

GIT Histology Links: Colon | Smooth Muscle Histology | Liver | Gall Bladder | Pancreas | Histology Stains | Histology | GIT Development

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 shows an automated computer PubMed search using the listed sub-heading term. Therefore the list of references do not reflect any editorial selection of material based on content or relevance. References appear in 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. Links: References | Discussion Page | Pubmed Most Recent Search term: Liver Embryology G V Bryukhin, M L Sizonenko The role of experimental maternal liver pathology in the development of physiological immaturity in the offspring. Bull. Exp. Biol. Med.: 2013, 154(5);591-3 PMID:23658875 Pei Xu, Dabing Li, Xiaotong Tang, Xiaohang Bao, Jing Huang, Yongping Tang, Yang Yang, Haiwei Xu, Xiaotang Fan LXR Agonists: New Potential Therapeutic Drug for Neurodegenerative Diseases. Mol. Neurobiol.: 2013; PMID:23625315 Tokio Katsumata, Hisashi Oishi, Yukari Sekiguchi, Haruka Nagasaki, Dhouha Daassi, Pei-Han Tai, Masatsugu Ema, Takashi Kudo, Satoru Takahashi Bioluminescence Imaging of β Cells and Intrahepatic Insulin Gene Activity under Normal and Pathological Conditions. PLoS ONE: 2013, 8(4);e60411 PMID:23593212 Hailong Lv, Yufeng Jiang, Xinyu Peng, Shijie Zhang, Xiangwei Wu, Hongqiang Yang, Hong Sun Echinococcus of the liver treated with laparoscopic subadventitial pericystectomy. Surg Laparosc Endosc Percutan Tech: 2013, 23(2);e49-53 PMID:23579528 Cynthia R Smith, Eric D Jensen, Brad A Blankenship, Mark Greenberg, Deborah A D'Agostini, Dolores H Pretorius, Nicholas C Saenz, Natalie Noll, Stephanie K Venn-Watson Fetal omphalocele in a common bottlenose dolphin (Tursiops truncatus). J. Zoo Wildl. Med.: 2013, 44(1);87-92 PMID:23505707

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 (More? Timeline human development)

Human data from Godlewski G, etal, see also liver development in the rat during the embryonic period (Carnegie stages 15-23).

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

Week 4-5

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 | Flash movies | Quicktime movies

Week 8

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 | Flash movies | Quicktime 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

Liver Movies

Lesser Sac	Greater Omentum
Quicktime version	Quicktime version

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

Takahiro Nakamura, Katsuya Sakai, Toshikazu Nakamura, Kunio Matsumoto Hepatocyte growth factor twenty years on: Much more than a growth factor. J. Gastroenterol. Hepatol.: 2011, 26 Suppl 1();188-202 PMID:21199531

Hisami Ando Embryology of the biliary tract. Dig Surg: 2010, 27(2);87-9 PMID:20551648

Janet W C Kung, Ian S Currie, Stuart J Forbes, James A Ross Liver development, regeneration, and carcinogenesis. J. Biomed. Biotechnol.: 2010, 2010();984248 PMID:20169172

Karim Si-Tayeb, Frédéric P Lemaigre, Stephen A Duncan Organogenesis and development of the liver. Dev. Cell: 2010, 18(2);175-89 PMID:20159590

John Le Lay, Klaus H Kaestner The Fox genes in the liver: from organogenesis to functional integration. Physiol. Rev.: 2010, 90(1);1-22 PMID:20086072

T Roskams, V Desmet Embryology of extra- and intrahepatic bile ducts, the ductal plate. Anat Rec (Hoboken): 2008, 291(6);628-35 PMID:18484608

Articles

Vincenzo Cardinale, Yunfang Wang, Guido Carpino, Gemma Mendel, Gianfranco Alpini, Eugenio Gaudio, Lola M Reid, Domenico Alvaro The biliary tree-a reservoir of multipotent stem cells. Nat Rev Gastroenterol Hepatol: 2012; PMID:22371217

Joshua R Friedman, Klaus H Kaestner On the origin of the liver. J. Clin. Invest.: 2011, 121(12);4630-3 PMID:22105167

Rodolphe Carpentier, Regina Español Suñer, Noémi van Hul, Janel L Kopp, Jean-Bernard Beaudry, Sabine Cordi, Aline Antoniou, Peggy Raynaud, Sébastien Lepreux, Patrick Jacquemin, Isabelle A Leclercq, Maike Sander, Frédéric P Lemaigre Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology: 2011, 141(4);1432-8, 1438.e1-4 PMID:21708104

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