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).
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.
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.