Danish researchers have discovered how the body makes the ducts that transport bile, enzymes and other secretions from the liver, gallbladder and pancreas to the intestine.
Researchers from the University of Copenhagen and the Francis Crick Institute in London have discovered how the body forms the ducts that transport various secretions from the liver, gallbladder and pancreas to the intestines.
The discovery provides new insights into the body’s plumbing system and can be used to better understand how a set of rare diseases occur.
In addition, the research uncovered genes that regulate the formation of the body’s plumbing system, which are associated with different types of cancer.
“This discovery is interesting, because it promises to help our understanding of what may cause the development of several diseases for which the underlying cause is currently poorly understood and that are difficult to treat,” says one author, Elke Ober, Associate Professor, Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen.
The study has been published in Nature Communications.
Blocked or narrow ducts can cause disease
The new study focused specifically on the bile duct and pancreatic duct. These two ducts transport bile and various digestive enzymes from the liver, gallbladder and pancreas to the intestine.
This usually happens in connection with a meal, when the various secreted enzymes and juices help with digestion.
The human ducts are together about 7 cm long, and are formed when the fetus is developing.
Unfortunately, the ducts are sometimes malformed, and if they are blocked, too narrow or even not formed at all, this can lead to diseases such as biliary atresia, in which the bile ducts are completely missing. In biliary atresia, the bile accumulates in the liver, which can cause liver damage, inflammation, chronic jaundice and, in the worst case, requires a liver transplant.
“In addition, the bile salts, which are important for digestion and absorbing fat, are not secreted into the gut, leading to additional physiological problems,” explains Elke Ober.
Zebrafish key to understanding the body’s ducts
To improve knowledge about these important ducts, Elke Ober and her colleagues investigated how they form anatomically and genetically.
In the anatomical study, the researchers used a high-resolution microscope that can capture images of 3D structures to examine how the ducts develop in zebrafish. The researchers chose zebrafish because their ducts form in 48 hours, whereas this takes several days or weeks in mice or people.
During this time, the liver, gallbladder, pancreas and ducts develop fully, and examining them under the microscope at different times of their development enabled the researchers to better understand the various stages of the formation process.
“Our choice of animal model is perfect for studying the development of these structures because they not only develop fast, but the overall anatomy of organs and functional cell types are also highly conserved between humans and zebrafish,” explains the first author, Ilcim Thestrup, who carried out her PhD studies at the Novo Nordisk Foundation Center for Stem Cell Biology, DanStem.
The researchers determined that the cells that later comprised the duct epithelium (lining) initially formed small lumina (openings) that slowly expanded until the entire bile duct was formed.
“One could imagine that the ducts might have formed by the intestinal cavity expanding and creating the duct into the liver. But we very clearly found that the cells themselves rearranged until an open bile duct was formed. This indicates which developmental processes can go wrong if the bile duct is not formed properly or if some cells block the duct,” says Elke Ober.
Specific genes control the plumbing system
The researchers followed up the anatomical study with a genetic study in which they discovered several of the genes involved and their significance.
They did this by using genome engineering to edit and inactivate a number of genes.
The researchers found these genes, belonging to the EphB and EphrinB families, control the behaviour of the cells in the ducts. Some create the bile duct to the liver, and others control the same process in the pancreas.
The research shows that the genes ephrinb2a and ephrinb1 represent two important signalling molecules, and the genes ephb3b and ephb4a are two important receptors: the “antennae” that capture the signals.
The two signalling molecules and their receptors control the movement of the cells when the ducts are formed. Initially, ductal cells are organized in a solid mass, and only when they start to rearrange, small spaces between the individual cells form and then gradually widen until the entire duct is open.
When the researchers inactivated some of these genes, specific parts of the ducts failed to form and open properly.
“This group of genes is important for making these ducts, but the cells of the duct from the liver are instructed by a different combination of these genes than the pancreatic duct cells. It is like an architectural drawing, each cell must thus follow its own instructions to form a specific part of the ductal system,” explains Elke Ober.
Elke Ober also says that the genes the researchers have linked to the formation of these ducts have already been associated with various forms of aggressive cancer. Failure to control these genes could be bad news.
Genes also discovered in human tissue samples
There is an evolutionary gap between newly hatched zebrafish and humans. Elke Ober and Jesper Bøye Andersen, Professor, Biotech Research and Innovation Centre (BRIC), University of Copenhagen therefore studied human tissue samples to determine whether these genes are active in human bile ducts.
They are, and the findings suggest that the same genes may control the formation of the ducts in humans, zebrafish and probably other animals with a liver and pancreas.
“This organ and connecting ductal system is highly conserved across species,” says Elke Ober.
In addition, she emphasizes that the researchers found the genes in tissue samples from adult humans, indicating that they may not only regulate the formation of these ducts as the fetus develops but may ensure their continued maintenance throughout life.
“A morphogenetic EphB/EphrinB code controls hepatopancreatic duct formation” has been published in Nature Communications. Elke Ober is employed at the Novo Nordisk Foundation Center for Stem Cell Biology, DanStem, University of Copenhagen.