By tracing the steps of liver regrowth, MIT engineers hope to harness the liver’s regenerative
abilities to help treat chronic disease.
The human liver has amazing regeneration capabilities: Even if up to 70 percent of it is removed,
the remaining tissue can regrow a full-sized liver within months.
Taking advantage of this regenerative capability could give doctors 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 involved in liver regeneration more precisely
than has been possible before.
The new model can yield information that couldn’t be gleaned from studies of mice or other animals,
whose biology is not identical to that of humans.
The researcher says that for years, people have been identifying different genes that
seem to be involved in mouse liver regeneration, and some of them seem to be important in humans,
but they have never managed to figure out all of the cues to make human liver cells
proliferate.
The new study, which appears in the jounral Proceedings of the National Academy of Sciences,
has identified one molecule that appears to play a key role, and also yielded several
other candidates that the researchers plan to explore further.
Most of the patients who need liver transplants suffer from chronic illnesses such as viral
hepatitis, fatty liver disease, or cancer.
However, if researchers had a reliable way to stimulate the liver to regenerate on its
own, some transplants could be avoided.
Or, such stimulation might be used to help a donated liver grow after being transplanted.
From studies in mice, researchers have learned a great deal about some of the regeneration
pathways that are activated after liver injury or illness.
One key 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 proliferate.
Another contributor that researchers have identified is fluid flow in the blood vessels.
In mice, an increase in blood flow can stimulate the endothelial cells to produce signals that
promote regeneration.
To model all of these interactions, the research team teamed up with a researcher who designs
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 so that molecules such as growth factors can flow between the blood
vessels and the liver spheroids.
This setup also allows the researchers to easily knock out 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 on its own did not
stimulate hepatocytes to enter the cell division cycle.
However, if they also delivered 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 earlier 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 knocking out 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 demonstrated that this
molecule stimulates human liver cells to enter the cell cycle.
The researchers now plan to further explore some of the other growth factors and molecules
that are produced on their chip during liver regeneration.
In this study, the researchers focused on molecules that stimulate cells to enter cell
division, but they now hope to follow the process further along and identify molecules
needed to complete the cell cycle.
They also hope to discover the signals that tell the liver when to stop regenerating.
Eventually researchers will be able to harness these molecules to help treat patients with
liver failure.
Another possibility is that doctors could use such factors as biomarkers to determine
how likely it is that a patient’s liver will regrow on its own.