From the time of Aristotle, it has been known that the human liver has the greatest regenerative capacity of any organ in the body, being able to regrow even from a 70% amputation, which has enabled live-donor transplants. Although the liver regenerates fully upon injury, the mechanisms that regulate how to activate or stop the process and when regeneration is terminated, are still unknown.
Researchers have now found that a regulatory cell type – mesenchymal cell – can activate or stop liver regeneration. The mesenchymal cells do so by the number of contacts they establish with the regenerating cells (epithelial cells). This study suggests that mistakes in the regeneration process, which can give rise to cancer or chronic liver diseases, are caused by the wrong number of contacts between both populations. The work is described in a paper published in the journal Cell Stem Cell.
The molecular mechanisms by which adult liver cells trigger the regenerative response remain largely unknown. Approximately 29 million people in Europe suffer from a chronic liver condition such as cirrhosis or liver cancer. They are a major cause of morbidity and mortality with liver diseases accounting for approximately two million deaths per year worldwide. Currently, there is no cure and liver transplants are the only treatment for liver failure. Scientists are therefore exploring new options for how to trigger the regenerative capacity of the liver as an alternative means to restore function.
Two main functional cells of the adult liver are hepatocytes, which perform many of the liver's functions, and ductal cells, which form the network of tiny ducts delivering bile to the intestine. These work in conjunction with other supporting cells, like the blood vessels or the mesenchymal cells.
For building liver organoids, in the beginning the researchers only used ductal cells of the bile duct. In order to improve this model and make it more similar to the real liver, the authors planned to build a more complex liver organoid that better mimics the cellular interactions and architecture of the adult liver tissue. For that they added liver mesenchyme – a type of regulatory cell of the connective tissue, which support the tubular structure of the bile duct.
“We put the mesenchymal cells next to the organoid, made out of the ductal cells, in a petri dish and saw that they were not touching or connecting, as they do in the native tissue” says the author. The author continues: “We were excited to see how our new and more complex organoid was recapitulating the tissue architecture in a dish, so we decided to study how the cells behave and filmed them under a microscope. To our surprise, we saw a totally unexpected behavior: the tissue (organoid) shrunk on touch with the mesenchymal cells but grew in the absence of contacts. This paradoxical behavior was very striking, but could help us explain why the tissue proliferated or stopped to do so during the regeneration process”.
In a healthy liver, there is a defined number of contacts between the ductal cells and the mesenchymal cells, which tells the ductal cells not to make more of themselves and just stay as they are. Once the tissue experiences damage, the mesenchymal cells decrease their number of contacts with the ductal cells, so they can multiply to repair the damage.
From their observation, the researchers concluded that rather than the absolute number of both cell types, it is the number of cellular contacts that controls how many cells are being produced to repair damaged tissue. Too many touches by mesenchymal cells means that fewer or no new ductal cells are being produced, and fewer touches means that more cells are being produced. This regulation is very important because when there is no signal for ductal cells to stop reproducing themselves to repair tissue, there could be over-production, which could lead to cancer.
Cell-to-cell contacts control liver regeneration
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