Prostaglandin E Switches Endoderm Cells From Pancreas to Liver


The gastrointestinal tract initially forms as a tube inside the embryo. Accessory digestive organs sprout from this tube in response to inductive signals from the surrounding mesoderm. Both the pancreas and the liver form at about the same time (4th week after fertilization) and at about the same place in the embryonic gut (the junction between the foregut and the midgut).

Pancreatic development

The pancreas forms as ventral and dorsal outgrowths that eventually fuse together when the gut rotates. The liver forms from the “hepatic diverticulum” that grows from the gut about 23-26 days after fertilization. These liver bud cells work with surrounding tissues to form the liver.

Liver development

What determines whether an endodermal cell becomes a liver or pancreatic precursor cell?

Wolfram Goessling and Trista North from the Harvard Stem Cell Institute (HSCI) have identified a gradient of the molecule prostaglandin E (PGE) in zebrafish embryos that acts as a liver/pancreas switch.

Postdoctoral researcher Sahar Nissim in the Goessling laboratory has uncovered how PGE toggles endodermal cells between the liver-pancreas fate. Nissim has shown that endodermal cells exposed to more PGE become liver cells and those exposed to less PGE become pancreas. This is the first time that prostaglandins have been reported as the factor that can switch cell identities from one fate to another.

After completing these experiments, HSCI scientists collaborated with colleague Richard Mass to determine if their PGE-mediated cell fate switch also occurred in mammals. Here again, Richard Sherwood from the Mass established that mouse endodermal cells became liver if exposed to PGE and pancreas if exposed to less PGE.  Sherwood also demonstrated that PGE enhanced liver growth and regeneration.

Goessling become interested in PGE in 2005, when a chemical screen identified PGE as an agent that amplified blood stem cell populations in zebrafish embryos. Goessling that transitioned this work to human patients, and a phase 1b clinical trial that uses PGE to increase umbilical cord blood transplants has just been completed.

PGE might be useful for instructing pluripotent human stem cells that have been differentiated into endodermal cells to form completely functional, mature liver cells that can be used to treatment patients with liver disease.

New 3D Method Used to Grow Miniature Pancreas


Researchers from the University of Copenhagen, in collaboration with an international team of investigators, have successfully developed an innovative three-dimensional method to grow miniature pancreas from progenitor cells. The future goal of this research is to utilize this model system to fight against diabetes. This research was recently published in the journal Development.

The new method allows the cell material from mice to grow vividly in picturesque tree-like structures.
The new method allows the cell material from mice to grow vividly in picturesque tree-like structures.

The new method takes cell material from mice and grows them in vividly picturesque tree-like structures.  The cells used were mouse embryonic pancreatic progenitors, and they were grown in a compound called Matrigel with accompanying cocktails of growth factors.  In vitro maintenance and expansion of these pancreatic progenitors requires active Notch and FGF signaling, and therefore, this culture system recapitulated the in vivo conditions that give rise to the pancreas in the embryo.

Professor Anne Grapin-Botton and her team at the Danish Stem Cell Centre, in collaboration with colleagues from the Ecole Polytechnique Fédérale de Lausanne in Switzerland, have developed a three-dimensional culture method that takes pancreatic cells and vigorously expands them. This new method allows the cell material from mice to grow vividly into several distinct picturesque, tree-like structures. The method offers tremendous long-term potential in producing miniature human pancreas from human stem cells. Human miniature pancreas organoids would be valuable as models to test new drugs fast and effectively, without the use of animal models.

“The new method allows the cell material to take a three-dimensional shape enabling them to multiply more freely. It’s like a plant where you use effective fertilizer, think of the laboratory like a garden and the scientist being the gardener,” says Anne Grapin-Botton.

In culture, pancreatic cells neither thrive nor develop if they are alone. A minimum of four pancreatic cells, growing close together is required for these cells to undergo organoid development.

“We found that the cells of the pancreas develop better in a gel in three-dimensions than when they are attached and flattened at the bottom of a culture plate. Under optimal conditions, the initial clusters of a few cells have proliferated into 40,000 cells within a week. After growing a lot, they transform into cells that make either digestive enzymes or hormones like insulin and they self-organize into branched pancreatic organoids that are amazingly similar to the pancreas,” adds Anne Grapin-Botton.

The scientists used this system to discover that the cells of the pancreas are sensitive to their physical environment, and are influenced by such seemingly insignificant factors as the stiffness of the gel and contact with other cells.

An effective cellular therapy for diabetes is dependent on the production of sufficient quantities of functional beta-cells. Recent studies have enabled the production of pancreatic precursors but efforts to expand these cells and differentiate them into insulin-producing beta-cells have proved a challenge.

“We think this is an important step towards the production of cells for diabetes therapy, both to produce mini-organs for drug testing and insulin-producing cells as spare parts. We show that the pancreatic cells care not only about how you feed them but need to be grown in the right physical environment. We are now trying to adapt this method to human stem cells,” adds Anne Grapin-Botton.