The Biliary Tree of Life

Researchers at the Diabetes Research Institute (DRI) have described a network of stem cells in the biliary tree, liver, and pancreas – and they are proposing to consider it as a framework for understanding liver and pancreas regeneration after extensive or chronic injuries.

Taking it one step further, they suggest that these stem cells should be considered for the study and treatment of diseases that affect these organs – such as type 1 diabetes. 

Mature Cells Fixing Minor Injuries … But What About Major Ones?
Replication of the functional ‘mature’ cells of the liver and pancreas ensures tissue repair after minor injuries. It has been suggested, however, that stem cells (very immature cells) and progenitors (quite immature cells) contribute to the fixing of more serious injuries, or more serious disease states.

Stem cells for the liver, biliary tree and pancreas are all generated when we are in our mothers’ bellies. 

After we are born, these stem cells do not disappear completely. Multiple aggregates of stem cells remain within a ramified network of ducts that direct digestive juices from the liver, gallbladder and pancreas, to the intestine (call this network of ducts “the biliary tree”).

If those stem cells remain there, there is probably a good reason.

A Tree of Life
The earliest, most immature (non-developed) stem cells seem to reside within the biliary tree. These stem cells are found in glands that are associated to bile ducts, primarily outside the liver. 

These biliary tree stem cells are made up of many subpopulations that can self-replicate and that can generate new mature cells. For instance, they can differentiate into mature liver cells and mature pancreatic cells. 

For people with type 1 diabetes, this is significant, because the ability of these biliary tree stem cells to give rise to pancreatic cells means there is the possibility to generate functional islet cells that produce insulin.

Wait! I’m not an Endocrinologist. Are you Saying Islet Cells Can Be Produced Outside the Pancreas?
DRI’s Giacomo Lanzoni, Ph.D., is calling for more research. The DRI team, that includes Dr. Luca Inverardi and Dr. Juan Dominguez-Bendala, is collaborating with Dr. Lola Reid’s group at the University of North Carolina at Chapel Hill, Dr. Eugenio Gaudio’s and Dr. D. Alvaro’s groups at La Sapienza University of Rome, and reported seminal findings in Hepatology and in Stem Cells. A review on the topic was recently published in Hepatology

Dr. Lanzoni says that the pancreas and the liver are two totally different organs – at least in humans. He notes, however, that there are animals (crabs, mollusks and some fishes) where the functions of liver and pancreas are actually provided by a single anatomical structure, called the “hepatopancreas.”

“So in Maine lobsters there are cells in the hepatopancreas that produce lobster insulin.” 

“And did you know that, in humans, insulin-producing cells also appear outside the pancreas?” says Dr. Lanzoni.  “… In humans the biliary tree, which is technically not the pancreas, can harbor insulin-producing cells.”

The biliary tree has many branches that penetrate the pancreas and liver. Lanzoni said it was very interesting to find insulin-producing cells naturally occurring within the biliary tree. 

“We have observed that the biliary tree hosts a large number of stem/progenitor cells that can give rise to a wide range of cells, including liver, biliary and pancreatic cells,” says Lanzoni. “What is really fascinating is the fact that these stem/progenitor cells can become insulin-producing cells.”

More research will be necessary to find out whether pancreatic islet beta cells and biliary tree beta-like cells function in the same way.

“But we have observed that human biliary tree-derived beta-like cells can release insulin in a glucose-responsive way and [fix] diabetes in animal models. And, well, that is great news!”

 X + Y+ Z
If biliary tree stem cells bear islet “fruit,” Dr. Lanzoni says that it will open up one more option from which islets could be obtained for people with diabetes.

“The more the merrier,” says Dr. Lanzoni. “The more stem and progenitor cells we can harvest from a donor, the better!”

To put it in simple terms, Dr. Lanzoni asks that we imagine ‘X’ as the amount of mature islets cells that can be harvested from a donated pancreas, and ‘Y’ and ‘Z’ as the amount of stem and progenitor cells that can be harvested from the biliary tree and the pancreas.

“I think that the transplantation of X+Y+Z would work much better than X alone, especially in the long term.”

The findings by Dr. Lanzoni and the DRI team also open up additional areas for investigation. 

“… We want to find out whether these stem/progenitor cells are present and active in type 1 diabetic patients, or if they are depleted due to – or in response to – the disease process”.

By Daniel Trecroci
March 2016

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