Researchers have developed a model in which they transplant liver cells into the eyes of mice, where the cells act in a similar way as in the liver. They can therefore be used to study liver disease, metabolic disorders and the effectiveness of treatments.
Studying the liver of living animals or humans is notoriously difficult because the only way is to remove it – but this only provides a snapshot of how the liver is doing.
Investigating liver function and the development of liver disease over time and at the cellular level are also impossible.
Researchers from the Karolinska Institutet have now tackled this problem by developing a new model that involves transplanting liver cells into the eyes of mice.
Intraocular liver cells act in the same way as in the liver, and this makes it much easier for researchers to monitor how the cells – and thus the liver – are doing and possibly in the future how treatments for people with certain liver diseases directly affect the liver cells.
“We now have an opportunity to study liver function and liver disease over time, which has not been possible before. We can thereby improve insight into the development of metabolic dysfunction–associated steatotic liver disease,” explains a researcher behind the development of this model system, Noah Moruzzi, Assistant Professor, Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
The researchers have published details of this model system and its potential in Nature Communications.
Studying liver disease directly in the eyes
The laboratory of Per-Olof Berggren at Karolinska Institutet, where the studies were carried out, previously created a similar model system for the insulin-producing islets of Langerhans, the regions in the pancreas that contain hormone-producing cells – a model system now used worldwide to study diabetes.
The new model gives researchers insight into the liver.
Researchers collect liver cells in a petri dish and then transplant them into the eyes of the mice.
The liver cells can be from another mouse or even from a person, which makes the model relevant in studies of liver disease involving humans.
In the petri dish, the liver cells form spheroids, which the researchers then transplant into the anterior chamber of mice’s eyes, where the spheroids attach themselves to the iris.
The researchers can then study the liver cells through the cornea – as a natural body window to examine liver function.
Creating a mini-liver in the eyes
The researchers show that the spheroids do not just stick to the iris but that they also establish blood supplies and nerve pathways with the surrounding tissue and begin to act like liver cells.
The liver cells also engage with the immune system and begin to change characteristics like real liver cells, and their genetic expression as measured by RNA expression also takes the form of a natural liver cell.
According to Noah Moruzzi, the liver cells might have changed their expression and started to look like something other than liver cells, but this does not seem to be the case.
“In most respects, the implanted cells look and act like liver cells. This is partly because they form these spheroids, and this makes us think that these liver cells provide a model of how the liver really acts,” he says.
Cells in the eyes act as liver cells
The researchers also show that what happens in the liver cells in the eyes of the mice also happens in the liver itself.
They found that feeding mice a high-fat and high-fructose diet causes the liver cells in both the liver and the eye to accumulate lipids, a characteristic of the development of metabolic dysfunction–associated steatotic liver disease (MASLD). The mouse model can thus be used to study this disease.
In this case, the researchers can study the liver cells in the eyes of the mice, thereby obtaining insight into what happens in the liver.
Testing whether drugs work as expected
Noah Moruzzi and Per-Olof Berggren think that researchers all over the world may be interested in using the newly developed model system for studying the liver, just as they have adopted the model for studying the islets of Langerhans.
They say that transplanting liver cells from humans into the eyes of the mice will enable researchers to study the early mechanisms behind the development of MASLD and how these early signs develop over time.
Diseases such as MASLD and type 2 diabetes have usually been associated with older people but are becoming more and more frequent among younger people who have obesity.
The development of the diseases and how interventions can slow down their development therefore need to be better understood.
“Importantly, this model system can be used to identify novel druggable targets and potential drugs for these targets. We can thereby investigate whether specific drugs appear to directly benefit the liver cells and can counteract the development of MASLD,” concludes Noah Moruzzi.
