Advanced organoid model generates complex liver architecture

Advanced organoid model generates complex liver architecture

The liver has a unique structure, particularly at the level of individual cells. Hepatocytes, the main liver cells, fill bile into tiny ducts called bile canaliculi, which drain into the bile duct in the liver's periportal region. When this bile drainage system is disrupted, it causes liver damage and disease. Because of this unique architecture, the study of liver disease has been limited by the lack of laboratory models that show exactly how the disease progresses, as it is difficult to recreate the complex structure and cell interactions of the liver in a dish. Existing tissue-derived liver organoid models consist of only one cell type and do not replicate the complex cellular composition and tissue architecture such as the liver periportal region.

The research group of Meritxell Huch, director at the Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, started this problem in a previous study in 2021,(Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation, Cordero-Espinoza, Lucía et al., Cell Stem Cell, Volume 28, Issue 11)Where the researchers developed a liver organoid consisting of two cell types, cholangiocyte and mesenchymal cells, capable of modeling cell-cell interactions and cell arrangement, but also other periportal cell types - primarily hepatocytes, the cell that builds the majority of the liver mass.

Creating a next-generation organoid model

In this recent study published in the journalNatureResearchers from the Meritxell Huch group, together with colleagues from the groups of Marino-Zerial and Heather Harrington, both also directors of the MPI-CBG, were able to develop a next-generation organoid model that they called a “Periportal Assembloid.” This assembloid has adult cholangiocytes and liver mesenchymal cells (as in the previous model), but also contains hepatocytes, which are the main functional cells of the adult liver. This model combines different cells that can be assembled in a step-by-step process that could be compared to LEGO.

"Our assembloid reconstructs the liver periportal region and can model aspects of cholestatic liver injury and biliary fibrosis. We specifically selected this region for a key role in bile transport. Often in liver diseases, when the connection of cells responsible for balance transport is blocked." Appointed assistant professor at the Technical University of Munich (Tum) in 2025.

"To achieve our goal, we first created organoids consisting only of hepatocytes, which formed functioning bile ducts and maintained key features of real hepatocytes in the tissue. Then we added cholangiocytes, which build cholangiocytes and fibroblast cells, to build periportal assemblers. Our liver model. Replicate the interactions between the different liver cells, "explains Aleksandra Sljukic, also first author of the study and a doctoral student in the Huch group.

By manipulating the number of mesenchymal cells, the researchers were able to trigger a reaction similar to liver fibrosis. They were also able to show that this model can be used to study the role of specific genes in liver disease by mixing normal and mutant cells or by turning off genes.

Using topological data analysis, Heather Harrington and her colleagues at the University of Oxford Forms Classifications of Assembly Bloids found that some forms correlated with better liver function over time.

Examination of liver disease and future vision

Meritxell Huch, who supervised and supervised the study, concludes: “We are pleased that we have been able to create a periportal assemblage model that combines for the first time a portal mesenchyme, cholangiocytes, cholangiocytes and hepatocytes, although some cells are still missing, namely structural periportal area in the scale of a tissue culture dish.

We envision that our periportal liver models may ultimately be used to study disease mechanisms. Once translated into human cells, it could be a way to move from 2D models used in pharmaceutical screenings to more physiological 3D models to study drug efficacy and toxicity in a more physiologically relevant context. “

Meritxell Huch, Director, Max Planck Institute for Molecular Cell Biology and Genetics

To the point:

New tissue-derived organoid model:A next-generation organoid model composed of three liver cell types—adult hepatocytes, cholangiocytes, and liver mesenchymal cells—reconstructs the liver periportal region.

Organoid functionality:The complex organoids or assembloids are functional and drain bile from the bile canaliculi into the bile duct as in the real liver due to their accurate recapitulation of the tissue architecture.

Liver Disease Modeling:This liver model reconstructs the architecture of the liver periportal region, can model aspects of cholestatic liver injury and biliary fibrosis, and demonstrates how different liver cell types contribute to liver disease.

Vision for the future:These periportal liver models could be used in the future to study the molecular and cellular mechanisms of liver disease. Once translated into human cells, they can enable efficacy and toxicity studies in a physiologically relevant context.

Sources: