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Research shows that liver or pancreas fated stem cells carry receptors on their outer membranes to detect the amount of prostaglandin E2 hormone present in the environment. The more prostaglandin the receptors detect, the cells become liver — the less prostaglandin, cells become the pancreas. Image Credit: University of Georgia, College of Verterinary Medicine

Cell fate switch that decides liver - or pancreas?

A cell’s fate, Harvard research found, is determined by the nearby presence of prostaglandin E2, a molecule best known for its role in inflammation and pain.

Harvard stem cell scientists have a new theory for how stem cells decide whether to become liver or pancreatic cells during development. Published in the journal Developmental Cell, the discovery could potentially make liver and pancreas cells easier to generate both in the lab and for cell therapies.

Wolfram Goessling, MD, PhD, and Trista North, PhD, both principal faculty members of the Harvard Stem Cell Institute (HSCI), identified a gradient of prostaglandin E2 in zebrafish embryos where stem cells differentiate into the internal organs.

Experiments conducted in the Goessling lab by Sahar Nissim, MD, PhD, showed that stem cells have specific receptors on their membranes to detect the amount of prostaglandin E2 hormone present. The receptors then coax the cell into differentiating into a specific organ.

“Cells that see more prostaglandin become liver and cells that see less prostaglandin become pancreas.

"This is the first time that prostaglandin is being reported as a factor leading this fate switch, essentially instructing what identity a cell will be.”

Wolfram Goessling, Harvard Medical School Assistant Professor, Medicine, Brigham and Women’s Hospital and Dana-Farber Cancer Institute.

Collaborating with the laboratory of HSCI Affiliated Faculty member Richard Maas, MD, PhD, Director of the Genetics Division at Brigham and Women’s Hospital, researchers wanted to see whether prostaglandin E2 has a similar function in mammals. Richard Sherwood, PhD, was successfully able to instruct mouse stem cells to become either liver or pancreas cells by exposing them to different amounts of the hormone. Other experiments showed that prostaglandin E2 could also enhance liver growth and regeneration of liver cells.

Goessling and his research partner North, a Harvard Medical School Assistant Professor of Pathology at Beth Israel Deaconess Hospital, first became intrigued by prostaglandin E2 in 2005. It caught their attention during the chemical exposure of 2,500 known drugs to zebrafish embryos, looking to see if any of the drugs would amplify blood stem cell populations.

Prostaglandin E2 was the most successful hit —the first molecule discovered to have such an effect—and recently successfully completed Phase 1b clinical trials as a therapeutic to improve cord blood transplants.

“Prostaglandin might be a master regulator of cell growth in different organs. It is used in cord blood, it works in the liver, and who knows what other organs might be affected by it.”

Wolfram Goessling, Harvard Medical School Assistant Professor, Medicine, Brigham and Women’s Hospital and Dana-Farber Cancer Institute.

With evidence of how prostaglandin E2 works in the liver, researchers next will calibrate what E2 amounts induce pluripotent stem cells — mature cells that have been reprogrammed back into a stem-like state — to become liver or pancreas determined cells. They believe that such a protocol could benefit patients needing liver cells for transplant or even for other organ injuries.

Highlights
PGE2 acts as a morphogen to regulate liver versus pancreas specification of endoderm
Expression of PGE2 pathway genes is patterned to regulate endoderm specification
PGE2 interacts with bmp2b signaling to promote a liver fate over a pancreas fate
PGE2 promotes organ growth later in development and liver regeneration in adults

Summary
The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here we describe prostaglandin E2 (PGE2) as a regulator of endodermal fate specification during development. Modulating PGE2 activity has opposing effects on liver versus pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE2 synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE2 synthesis acquire a liver fate, whereas more distant cells acquire a pancreas fate. PGE2 interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE2 acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE2 remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE2 may act as a morphogen to regulate cell-fate decisions and outgrowth of the embryonic endodermal anlagen.

Authors
Sahar Nissim, Richard I. Sherwood, Julia Wucherpfennig, Diane Saunders, James M. Harris, Virginie Esain, Kelli J. Carroll, Gregory M. Frechette, Andrew J. Kim, Katie L. Hwang, Claire C. Cutting, Susanna Elledge, Trista E. Northsend email, Wolfram Goessling

The work was supported by the Harvard Stem Cell Institute, the National Pancreas Foundation, the National Institutes of Health, and the Pew Charitable Trusts.