To further refine the model, the team collaborated with Heather Harrington and her colleagues at the University of Oxford. Using topological data analysis—a branch of mathematics that looks at the "shape" of data—the researchers were able to classify the various shapes the assembloids took. They discovered that certain structural configurations correlated with better liver function over time, providing a quantitative way to measure the success of their lab-grown tissues.
Vision for the Future of Pharmaceutical Testing
While the current periportal assembloids are a landmark achievement, the researchers acknowledge that there is still work to be done. The current model includes the primary structural and functional cells of the periportal region, but it does not yet incorporate the endothelium (blood vessel lining) or immune cells, both of which play roles in liver health and inflammation.
Nevertheless, the "all-in-one" nature of the model makes it a powerful asset for the future of drug development. Currently, the pharmaceutical industry relies heavily on 2D cell cultures for initial drug screenings. These models are often poor predictors of how a drug will behave in a human body because they lack the 3D architecture and cell-to-cell signaling of real tissue. This discrepancy often leads to drugs failing in late-stage clinical trials due to unforeseen toxicity or lack of efficacy.
Meritxell Huch envisions a future where these assembloids serve as a more reliable bridge between the laboratory and the clinic. "We are excited that we were able to create a periportal assembloid model that combines, for the first time, portal mesenchyme, cholangiocytes, and hepatocytes," Huch says. "Its modular features allow it to be easily studied, handled, and manipulated in the lab."
The ultimate goal is to translate these findings using human-derived cells. If successful, these patient-specific assembloids could be used to test how a particular individual might respond to a drug, ushering in a new era of personalized medicine for liver disease. "Once translated to human cells, it could be a way of moving from 2D models utilized in pharmaceutical screenings to more physiological 3D models to study drug efficacy and toxicity in a more physiologically relevant context," Huch concludes.
As the scientific community continues to move away from animal testing and toward more human-centric models, the development of the periportal assembloid stands as a testament to the power of interdisciplinary collaboration. By combining biology, engineering, and mathematics, the researchers at MPI-CBG have not only built a better model of the liver—they have provided a roadmap for reconstructing the complex beauty of human physiology in a dish.
