Tissue model reveals key players in liver regeneration

Newswise – CAMBRIDGE, MA – The human liver has amazing regenerative capabilities: Even if up to 70 percent of it is removed, the remaining tissue can grow into a full-sized liver within months.

Taking advantage of this regenerative ability could provide doctors with many more options for treating chronic liver disease. MIT engineers have now taken a step toward that goal by creating a new liver tissue model that allows them to trace the steps in liver regeneration more accurately than was previously possible.

The new model may provide information that cannot be obtained from studies of mice or other animals, whose biology is not identical to that of humans, said Sangeeta Bhatia, the leader of the research team.

“For years, people have identified several genes that appear to be involved in mouse liver regeneration, and some appear to be important in humans, but they have never been able to figure out all the clues to allow human liver cells to proliferate,” says Bhatia, the John and Dorothy Wilson professor of health sciences and technology and electrical and computer sciences at MIT and a member of the MIT Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

The new study, published this week in the Proceedings of the National Academy of Scienceshas identified one molecule that appears to play a key role, as well as yielding several other candidates that the researchers plan to explore further.

The paper’s lead author is Arnav Chhabra, a former MIT graduate student and postdoc.

Regeneration on a chip

Most patients who need a liver transplant suffer from chronic diseases such as viral hepatitis, fatty liver or cancer. However, if researchers had a reliable way to stimulate the liver to regenerate itself, some transplants could be avoided, Bhatia says. Or such stimulation could be used to help a donated liver grow after a transplant.

From studies in mice, researchers have learned a lot about some of the regeneration pathways that are activated after liver injury or disease. An important factor is the reciprocal relationship between hepatocytes (the main type of cell found in the liver) and endothelial cells, which line the blood vessels. Hepatocytes produce factors that help blood vessels develop, and endothelial cells generate growth factors that help hepatocytes multiply.

Another contributor that researchers have identified is the flow of fluid in the blood vessels. In mice, an increase in blood flow can stimulate endothelial cells to produce signals that promote regeneration.

To model all of these interactions, Bhatia’s lab teamed up with Christopher Chen, the William F. Warren Distinguished Professor of Biomedical Engineering at Boston University, who is designing microfluidic devices with channels that mimic blood vessels. To create these models of “regeneration on a chip,” the researchers grew blood vessels along one of these microfluidic channels and then added multicellular spheroid aggregates derived from liver cells from human organ donors.

The chip is designed in such a way that molecules such as growth factors can flow between the blood vessels and the liver spheroids. This setup also allows the researchers to easily turn off genes of interest in a specific cell type and then see how it affects the overall system.

Using this system, the researchers showed that increased fluid flow by itself did not stimulate hepatocytes to enter the cell division cycle. However, if they also released an inflammatory signal (the cytokine IL-1-beta), hepatocytes did enter the cell cycle.

When that happened, the researchers were able to measure what other factors were being produced. Some were expected based on previous mouse studies, but others had not been seen before in human cells, including a molecule called prostaglandin E2 (PGE2).

The MIT team found high levels of this molecule, which is also involved in zebrafish regeneration, in their liver regeneration system. By turning off the gene for PGE2 biosynthesis in endothelial cells, the researchers were able to show that those cells are the source of PGE2, and they also showed that this molecule stimulates human liver cells to enter the cell cycle.

Human-specific paths

The researchers now plan to further investigate some of the other growth factors and molecules produced on their chip during liver regeneration.

“We can look at the proteins that are produced and ask ourselves, What else on this list has the same pattern as the other molecules that stimulate cell division, but is it new?” says Bhatia. “We think we can use this to discover new human-specific pathways.”

In this study, the researchers focused on molecules that stimulate cells to enter cell division, but they now hope to follow the process further and identify molecules needed to complete the cell cycle. They also hope to discover the signals that tell the liver when to stop regenerating.

Bhatia hopes that eventually researchers can use these molecules to help treat patients with liver failure. Another possibility is that doctors could use factors such as biomarkers to determine the likelihood of a patient’s liver growing back on its own.

“Right now, when patients come in with liver failure, you have to transplant them because you don’t know if they will recover on their own. But if we knew who had a strong regenerative response, and if we just stabilized them for a while, we could save those patients a transplant,” Bhatia says.

The research was funded in part by the National Institutes of Health, the National Science Foundation Graduate Research Fellowship Program, Wellcome Leap and the Paul and Daisy Soros Fellowship Program.


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