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The liver is essential to our health, helping to maintain balance in the body, from detoxifying our blood to storing and releasing nutrients. Its smooth surface conceals a surprisingly high degree of complexity.
“The organs in our body are not just bags of cells,” says LSO project coordinator Shaul Shalev Itzkovitz, professor at the Weizmann Institute of Science in Israel. “The intestine, the liver, the pancreas are highly structured, composed of repeating anatomical units.”
In the liver, hepatocytes work within millimetre-sized hexagonal structures called lobules, which are arranged based on blood flow and signalling molecules. This set-up, known as ‘liver zonation’, helps localise different tasks to specific areas of the lobules. However, new research shows that about 50 % of liver genes are active only in specific zones. This raises an important question: are hepatocytes the same everywhere, and simply responding to local signals, or are there actually different cell types in each zone?
Supported by the European Research Council (ERC), Itzkovitz and his team used a variety of groundbreaking techniques, such as spatial sorting, clump sequencing, and paired-cell RNA sequencing, to build the most precise view to date of the liver, delivering key findings with potential applications for human health.
Healing help
When tissue is damaged, you might expect cells closest to the wound to divide and bridge the gap. But Itzkovitz and his team found something very different in the liver, helping to explain its prodigious healing ability. “Hepatocytes are dividing not only at the border of the damaged area, but all over the liver. If all of them divide, then you can close the wound very rapidly, because you create new hepatocytes that are pushing inwards,” he notes.
Crucially, these migrating cells quickly ‘forget’ their previous identity and role in the organ and re-specialise to perform the appropriate activity in their new location, a property called plasticity. The work sheds light on how we can help patients recover from liver damage caused by poisoning or harsh medications such as chemotherapy.
Organ mapping
A deeper understanding of how the liver is structured could help in the treatment of illnesses such as poisoning, cirrhosis and malaria. The team developed a single-cell atlas of the Plasmodium liver stage, mapping how the malaria-causing parasite behaves during this critical part of its life cycle.
“The very first step of malaria infection is that the parasites get into the bloodstream and must enter the liver, where they settle in a hepatocyte,” explains Itzkovitz. These cells act as a sanctuary for the parasites, which divide until tens of thousands of parasites are released back into the blood.
However, the malaria parasite does not simply infect the first hepatocyte it finds. “It enters, and then it drills within the walls and goes into three hepatocytes on average before it settles and starts to divide,” reveals Itzkovitz.
His team found that those parasites that made it into the inner layers of the lobules were far more successful at reproduction. The discovery could lead to new malaria treatments that prevent the malaria parasite from infecting preferred cells.
Cell identification
Examining the intestine, the team were able to show how the migration of cells across the gut wall was so rapid that it obscured the microstructure of the tissue. “Basically, if you look at the RNA and try to infer what cells at different locations do, you would get a different picture than if you examined the proteins,” adds Itzkovitz.
The LSO project was also able to develop techniques to identify where shed cells originated in an organ’s microstructure. This offers clinicians a much higher degree of sophistication when making diagnoses from cell material found in blood or stool samples.
Itzkovitz says the project highlights the value of the ERC grant structure. “We started with liver heterogeneity, but we took the same concepts and then extended them to other organs and to other modalities that are evolving all the time. This flexibility is really nice, because it enables you to explore new directions.” His work continues under ZONESHED, an ERC-supported proof of concept project that aims to use the techniques developed under LSO to more accurately diagnose liver damage in human patients.