New Insights into the Immune Cells of the Liver
The liver plays a central role in the body’s metabolism and immune regulation. Yet, many cellular mechanisms involved in liver diseases remain only partially understood. Researchers from Charité, Si-M – The Simulated Human and the Cincinnati Children’s Hospital Medical Center have now gained crucial insights into the molecular processes underlying liver function. The study provides new approaches for understanding and targeted treatment of liver diseases. In this interview, Dr. Milad Rezvani, the study’s lead author and alumnus of the BIH Charité Clinician Scientist “Excellence Track” discusses the findings.
What question did you want to answer, what were you particularly interested in?
Organoids—three-dimensional mini-organ models derived from human cells—have been used successfully for several years to study liver diseases in a realistic way. However, a key aspect of many liver conditions is the inflammatory immune response, which traditional organoid models cannot authentically reproduce.
We were therefore especially interested in whether it is possible to develop human liver organoids that not only mimic liver tissue but also contain their own functionally integrated immune system. Our goal was to investigate the complex interactions between liver and immune cells under the most realistic conditions possible, to better understand disease mechanisms.
What specific challenges did you face when developing your approach?
The greatest challenge was to combine different human cell types—especially liver and immune cells—into a “2-in-1 system” that allows them to develop stably and interact functionally within a single organoid. We also needed to establish conditions that permitted immune reactions without destabilizing or artificially altering the delicate organoid system.
What surprised you and why? What was new?
We were surprised by how well the liver and immune system self-organized in the dish once the right initial conditions were established. After being guided with growth factors for only about ten days, the organoids continued to develop autonomously.
Remarkably, the liver organoids began to form blood-producing structures and immune cells “on their own.” We suddenly observed red blood islands as well as white immune cells within the organoids. Such a coordinated, spontaneous co-development of liver, blood, and immune systems has never been described in any other organoid model.
What significance could this success have for future patients?
This success could make it possible to study liver diseases much more realistically and develop targeted therapies against liver injuries involving inflammation. In the long term, such organoids could help predict disease progression on an individual basis, test drugs in a personalized manner, and design new treatment strategies.
Where do you see the translational bridge between research and application?
In our publication, for example, we demonstrated that an "organoid diet" high in fat activated part of the immune system through a molecule absent in mice. This molecule, IL-8, triggered neutrophils, which in turn caused inflammatory damage to the liver tissue. We now plan to investigate whether IL-8 plays a role in the progression from fatty liver disease to inflammation and cirrhosis.