Scientists have found the reason for the loss of the liver's ability to regenerate
The liver is considered the only major human organ capable of almost complete recovery, even after serious damage. However, with alcoholic liver disease, this mechanism sometimes stops working — even if a person has completely given up alcohol.
A new study has shown that chronic inflammation can disrupt an important process inside cells, which is why they find themselves in a kind of "regenerative impasse" and are unable to complete tissue repair. How alcohol disrupts the natural regeneration of the liver and why the discovery may help in the development of new treatment methods — in the Izvestia article.
Why does the liver stop recovering
The study is published in the journal Science Daily. The work is devoted to alcohol-associated liver disease, one of the leading causes of death from diseases of this organ worldwide. According to researchers, it is associated with about 3 million deaths annually.
Aoinash Kalsotra, Professor of biochemistry at the University of Illinois and head of the study
We knew that patients with alcoholic hepatitis and cirrhosis of the liver stop functioning and regenerating, even if the patient stopped drinking alcohol, but we did not know why.
According to him, today, with severe liver failure, the only way to save a patient's life is often transplantation. That is why understanding the reasons why the liver stops recovering on its own may open up new possibilities for treating the disease.
How the liver repairs itself after damage
The ability to regenerate is considered one of the most unusual features of the liver. Unlike most organs of the human body, it can restore the lost volume even after significant damage or surgical removal of part of the tissue. It is this ability that allows the liver to maintain its functions for a long time, even under severe stress.
As the authors explain, normally mature liver cells don't just start dividing. At first, they temporarily change their "specialization" and return to a state resembling the progenitor cells characteristic of the early stages of an organism's development. Such cells are able to actively multiply and replenish lost tissue. After the regeneration is completed, they become mature liver cells again and continue to perform their functions.
The research group has been studying this mechanism for several years. In previous work, scientists have shown that during liver repair, cells temporarily rearrange their genetic program and begin using a different set of genes. It was this discovery that prompted researchers to find out what happens with alcoholic liver disease and why this process suddenly stops.
For the new work, the specialists compared healthy liver samples with the tissues of patients suffering from alcoholic hepatitis and cirrhosis. The analysis showed that the cells are really trying to go into recovery mode, but at one stage this process stops.
Cells find themselves in a "regenerative dead end"
A comparison of healthy liver tissues with samples from patients with alcoholic hepatitis and cirrhosis revealed an unexpected pattern. It turned out that the damaged cells are really trying to start the recovery process.: they begin to return to the state necessary for regeneration. However, they are unable to complete this transition. Instead, the cells are literally "stuck" between two states — they are no longer full-fledged mature cells, but they have not yet become progenitor cells capable of actively dividing and repairing tissue.
This creates a kind of vicious circle. Cells that are in an intermediate state can no longer fully perform the functions of the liver. Then the load falls on the remaining healthy cells, which are also trying to switch to regeneration mode. But they are gradually falling into the same "trap". As a result, the number of normally functioning cells decreases, and organ repair actually stops.
Ullas Cembazhi and Sushant Bangr, graduate students at the University of Illinois and co-authors of the study
They are neither functional adult cells nor proliferative progenitor cells. Since they are not functioning, additional pressure is put on the remaining cells. Therefore, they try to regenerate, and eventually they all end up in this unproductive quasi-progenitor state, which causes liver failure.
To understand what prevents cells from completing repair, the researchers studied the process of RNA splicing, the stage at which the cell "edits" RNA molecules before synthesizing proteins. It turned out that in alcoholic liver disease, this mechanism is disrupted in thousands of genes at once, which is why many proteins either work incorrectly or cannot perform their functions at all.
Chronic inflammation disrupts the functioning of liver cells
Further analysis showed that one of the key causes of these disorders is a deficiency of the ESRP2 protein. Normally, it binds to RNA and helps to correctly "assemble" genetic instructions, which are then used to synthesize proteins. However, the level of ESRP2 was significantly reduced in the cells of the damaged liver.
The consequences turned out to be much more serious than the researchers had anticipated. Even when the cell continued to produce the required amount of proteins, many of them ended up in the wrong part of the cell where they were supposed to work. For example, the proteins responsible for regeneration remained in the cytoplasm instead of moving to the nucleus and regulating the activity of genes.
Aoinash Kalsotra
Proteins work only in a strictly defined place of the cell — this is determined by the sequences inside the protein that move it to a specific location. We found that the sequences determining their location were disrupted. <...> The amount of RNA and protein was the same, but the protein was not in the place where it should function. Due to the disruption of splicing, key proteins necessary for productive liver regeneration were stuck in the cytoplasm, whereas they needed to be in the nucleus.
The researchers also found out why the level of ESRP2 is decreasing. During alcohol processing, liver tissues are damaged, in response to which immune cells and other cells of the microenvironment actively migrate to the organ. They secrete a large number of inflammatory molecules and growth factors that inhibit the formation and activity of ESRP2. According to the authors, it is chronic inflammation that triggers a chain of events that disrupt liver regeneration.
To test this hypothesis, the scientists treated liver cells with a molecule that blocks the receptor of one of the inflammatory factors. After that, the level of ESRP2 recovered, and the process of RNA splicing began to occur much more correctly again, which makes this signaling pathway a potential target for future drugs.
What discovery can change in treatment
The authors believe that the results of the study can be useful in several directions at once. First, improperly processed RNA molecules can potentially be used as biomarkers that can detect severe forms of alcoholic liver disease or monitor the progression of the disease. Secondly, instead of trying to repair already destroyed tissue, future treatments may be aimed at eliminating inflammatory signals that prevent the liver from completing its natural regeneration.
To verify their findings, the researchers also studied mice that lacked the gene responsible for the production of ESRP2. The rodents developed the same liver regeneration disorders as in patients with severe alcoholic hepatitis. This confirmed that protein deficiency does play an important role in the development of the disease.
Aoinash Kalsotra
I hope that these results will serve as a starting point for future clinical trials. We can use improperly processed RNA molecules as diagnostic markers or develop treatments that reduce inflammation. If we can correct the splice disorders, perhaps we can improve recovery and restore the damaged liver's ability to regenerate.
So far, the work has been performed on human tissue samples, cell cultures, and experimental models, so additional research is needed before new treatment methods become available. Nevertheless, the authors believe that for the first time it has been possible to explain in detail why the liver of some patients stops recovering even after complete abstinence from alcohol, as well as to identify a specific molecular target, which in the future may help restore the organ's ability to regenerate naturally.
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