To researchers at the Karolinska Institute, the eyes are not just organs of vision, but portals to understanding organ function. Since 2008, experimental endocrinologist Per-Olof Berggren’s research group has been transplanting pancreatic islets into the anterior chamber of the eye to monitor insulin production during type 2 diabetes in mice (1). About 16 years later, they are turning the eye into a liver-monitoring platform. 

In a study published in Nature Communications, the scientists reported that they could implant liver spheroids into the eyes of mice to track liver function (2). This method is superior to three-dimensional culture models, which lack anatomical features, and highlights the utility of liver spheroids as a model for studying liver disease.

Transplanting foreign objects into the eye is an 151-year-old idea. In 1873, German scientists transplanted cork and paper pieces and human and animal skin into the eyes of rabbits and dogs, which became a useful eye injury model (3). “Transplanting liver spheroids in the eye is definitely new,” said Midhat Abdulreda, an immunologist at the University of Miami who was not involved with the study. Abdulreda has been transplanting pancreatic islets into the mouse eye for 15 years. “It's great to see that the work is being expanded to include other [cell] types because this is exactly what we have tried to do throughout the years.” 

It’s like having an organ-on-a-chip, but it’s in the animals. 
- Noah Moruzzi, Karolinska Institute

Berggren’s group started by culturing liver spheroids and injecting them into the irises of mice via the cornea. The spheroids integrated into the eye’s vasculature and developed features of mature liver cells, including gene expression and characteristic proteins. They also retained their ability to perform characteristic liver functions, including bile and lipid metabolism. “It’s like having an organ-on-a-chip, but it’s in the animals,” said endocrinologist and study coauthor Noah Moruzzi.

Currently, liver in vivo imaging is underdeveloped, making it challenging to monitor liver functions without terminal procedures. However, with this platform, liver spheroids can be monitored non-invasively for extended periods, offering a unique advantage in toxicity studies. “Liver spheroids have been a big interest for pharma because the liver is involved in metabolizing drugs, so it’s an important screening platform,” said Abdulreda. 

Tracking liver health as a function of diet is another potential application. In their study, they fed mice a high-fat-high-fructose diet for 12 weeks and tracked lipid accumulation over time in the transplanted liver spheroids in the eye. Mice accumulated lipid droplets in their transplanted liver cells to a similar extent as in their livers.

In future experiments, Moruzzi hopes to expand the menu of applications, particularly for liver regeneration studies. “If you transplant hepatocytes to the lymph nodes, and you cut a piece of the liver, they start to proliferate in the lymph node,” he said. “We think we can induce liver proliferation in the eye.” In unpublished data, they recorded liver cell proliferation in the eye in response to liver stimulation. “There are many possibilities that deserve attention and for which we don't have answers yet,” he said. 

References

1. Speier, S. et al. Noninvasive in vivo imaging of pancreatic islet cell biology. Nat Med  14, 574–578 (2008).
2. Lazzeri-Barcelo, F. et al. Intraocular liver spheroids for non-invasive high-resolution in vivo monitoring of liver cell function. Nat Commun  15, 767 (2024).
3. Dooremaal, J. C. Die Entwickelung der in fremden Grund versetzten lebenden Gewebe. Albrecht Von Græfes Arch Für Ophthalmol  19, 359–373 (1873).