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, consistently draining bile from the bile canaliculi into the bile duct as in the real liver due to their accurate tissue architecture recapitulation.
Liver disease modelling: This liver model reconstructs the liver periportal region architecture, is able to model aspects of cholestatic liver injury and biliary fibrosis, and can show 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 to human cells, they might enable drug efficacy and toxicity studies in a more physiologically relevant context.
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The liver has a unique structure, especially at the level of individual cells. Hepatocytes, the main liver cells, release bile into tiny channels called bile canaliculi, which drain into the bile duct in the liver periportal region. When this bile drainage system is disrupted, it causes liver damage and disease. Because of this unique architecture, liver disease investigation has been limited by the lack of lab-grown models that accurately show how the disease progresses, as it is challenging to recreate the liver's complex structure and cell interactions in a dish. Existing tissue-derived liver organoid models consist of only one cell type and fail to 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 of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, Germany, started to address this issue 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 mesenchyme cells, which was able to model cell-cell interactions and cell arrangement, but still lacked other periportal cell types – most importantly hepatocytes, the cell which builds the majority of liver mass.
Creating a next-generation organoid model
In this current study, published in the journal Nature, researchers from the group of Meritxell Huch, together with colleagues from the groups of Marino Zerial and Heather Harrington, both also directors at the MPI-CBG, were able to develop a next-generation organoid model, which they named “periportal assembloid.” This assembloid features adult cholangiocytes and liver mesenchymal cells (as in the previous model), but now additionally also includes hepatocytes, which are the main functional cells of the adult liver. This model combines different cells assembled together in a stepwise process one could compare to LEGO.
“Our assembloid reconstructs the liver periportal region and can model aspects of cholestatic liver injury and biliary fibrosis. We chose this region in particular since it plays a key role in bile transport and is often disrupted in liver diseases when the connection of cells responsible for bile transport is blocked,” says Anna Dowbaj, one of the first authors, postdoctoral researcher in the Huch group, and from June 2025 appointed assistant professor at the Technical University of Munich (TUM).
“To achieve our goal, we first created organoids only consisting of hepatocytes that formed working bile channels and maintained key features of real hepatocytes in the tissue. Then, we added cholangiocytes and fibroblast cells to build periportal assembloids. Our liver model works like real liver tissue, moving bile from inside the liver cells into bile ducts, which shows that we were able to 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 response similar to liver fibrosis. They also were able to show that this model can be used to study the roles of specific genes in liver disease by mixing normal and mutated cells or by turning genes off.
Using topological data analysis, Heather Harrington and her colleagues at the University of Oxford classified assembloids’ shapes and found that some shapes correlated with better liver function over time.
Studying liver diseases and a future vision
Meritxell Huch, who oversaw and supervised the study, concludes, “We are excited that we were able to create a periportal assembloid model that combines, for the first time, portal mesenchyme, cholangiocytes, and hepatocytes. Although some cells are still missing, namely the endothelium and immune cells, the model captures with high precision the cellular and structural architecture of the liver's periportal area at the scale of a tissue culture dish. Additionally, its modular features allow it to be easily studied, handled, and manipulated in the lab. Our liver assembloids are the first all-in-one lab model that can be used to study bile flow, bile duct injury, and how different liver cells contribute to disease.”
Meritxell Huch continues, “We envision that our periportal liver models can ultimately be used to study disease mechanisms. 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.”
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