In this project, we set out to create a lab model that better mimics how liver disease develops in the body. Studying liver disease in a dish requires systems that truly reflect the liver's structure and cell types, but current models often fall short. They typically don’t capture the full range of liver cells or the way those cells are organized and interact.
To address this, we developed a new 3D liver model made from several types of adult human liver cells: hepatocytes (the main liver cells), cholangiocytes (which line the bile ducts), and mesenchymal cells (which provide structural support). Together, these cells form a model that recreates the periportal region of the liver—a key area involved in bile production and flow. This allows us to study diseases like cholestasis (bile flow blockage) and liver fibrosis (scarring).
We first grew hepatocyte organoids with a working network of tiny bile channels that closely resemble those found in real liver tissue. Then, by combining these with bile duct cells and support cells, we built more complete "liver assembloids" that allow the cells to interact in realistic ways. These assembloids successfully moved bile from the liver cells into bile ducts, showing functional bile drainage.
Interestingly, we discovered that simply increasing the number of support cells (mesenchymal cells) was enough to trigger a scarring-like response, even without involving immune cells. To explore how specific genes and cell types affect liver disease, we also created assembloids with a mix of normal and genetically altered cells.
Overall, in this project, we built a detailed and realistic liver model that can be used to study how bile flows through the liver, how liver scarring begins, and how individual cell types and genes contribute to disease.
