Incredible Regeneration of the Liver

MIT Liver Regeneration Press
By tracing the steps of liver regrowth, MIT engineers hope to leverage the liver's regenerative abilities to help treat chronic diseases. The hepatocytes pictured are the main functional cells of the liver. Credit :Image: NIH

The human liver has incredible regenerative abilities: Even with up to 70 percent removed, the remaining tissue can regrow as a full-size liver within months. This regenerative ability of the liver could offer the medical community more options for treating chronic liver disease. MIT engineers took a step towards this goal by creating a new liver tissue model in liver regeneration.

With this model, the researchers aim to follow previous work and steps in the subject more precisely than is possible.

Sangeeta Bhatia, leader of the research team, says the new model could provide insights that could not be gleaned from studies of mice or other animals whose biology is not the same as humans.

“For years, people have been identifying different genes involved in mouse liver regeneration, and some of them seem to be important in humans, but they've never been able to unravel all the clues that make human liver cells proliferate,” the researchers say.

Sangeeta Bhatia is a Fellow of the Broad Institute of MIT and Harvard Institute. The paper's lead author is Arnav Chhabra, a former MIT graduate student and postdoctoral fellow.

The new study, which appears this week in the Proceedings of the National Academy of Sciences, has identified a molecule that appears to play a key role. However, there are several other issues to be explored.

Most patients who need liver transplants suffer from chronic diseases such as viral hepatitis, fatty liver disease or cancer.

However, Bhatia says some transplants could have been avoided if researchers had a reliable way to stimulate the liver to self-regenerate. Or this type of stimulus could be used to help a donated liver grow after it has been transplanted.

From studies in mice, researchers have learned a lot about certain regeneration pathways that are activated after liver injury or disease.

One of the key factors is the interrelationship between hepatocytes (the main cell type found in the liver) and the endothelial cells lining blood vessels.

Hepatocytes produce factors that help blood vessels develop, and endothelial cells produce growth factors that help hepatocytes proliferate.

Another contribution the researchers identified is the flow of fluid in the blood vessels. An increase in blood flow in mice can stimulate endothelial cells to produce signals that promote regeneration.

To model all these interactions, Bhatia worked with Christopher Chen at Boston University, who designed microfluidic devices with channels that mimic blood vessels.

To create these “regeneration-on-a-chip” models, the researchers enlarged blood vessels through one of these microfluidic channels and then added multicellular globular clusters derived from liver cells from human organ donors.

The chip is designed so that molecules such as growth factors can flow between blood vessels and liver spheroids.

This setup also allows researchers to easily disable relevant genes in a particular cell type and then see how this affects the overall system.

Using this system, the researchers showed that the increased fluid flow alone does not encourage hepatocytes to enter the cell division cycle. However, if they also transmitted an inflammatory signal (cytokine IL-1-beta), hepatocytes entered the cell cycle.

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

The MIT team found high levels of this molecule in liver regeneration systems, which is also involved in zebrafish regeneration.

By deactivating the PGE2 biosynthesis gene in endothelial cells, the researchers were able to show that these cells are the source of PGE2, and they also showed that this molecule stimulates human liver cells to enter the cell cycle.

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

Sangeeta Bhatia's statements continue as follows;

“We could look at the proteins produced and ask what else is on this list that has the same structure as other molecules that stimulate cell division, but is new? We think we can use this to explore new human ways.”

In this study, the researchers focused on molecules that stimulate cells to enter cell division, but they now hope to further follow the process and identify the molecules needed to complete the cell cycle.

They also hope to discover signals that tell the liver when to stop regenerating.

Bhatia hopes that researchers will eventually be able to use these molecules to help treat patients with liver failure.

Another possibility is that doctors can use factors such as biomarkers to determine the likelihood of a patient's liver regrowth 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 get better on their own. But if we knew who had a strong regenerative response and needed to stabilize them for a while, we could save these patients from transplant,” says Bhatia.

Source: MIT News

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