Periodic Reporting for period 1 - REG_ORGatSCALE (Mechanisms of liver regeneration and disease across scales; from molecules to cells and tissue)
Berichtszeitraum: 2023-05-01 bis 2025-10-31
In this project, we aim to better understand how the liver repairs itself and why, in some cases, this process goes wrong and leads to disease. Even though there have been recent scientific advances, the basic rules behind liver regeneration—and how their failure can cause illness—are still not fully understood.
Our main goal is to uncover the key molecular and cellular processes that control how the liver regenerates after damage. We also want to use this knowledge to build more advanced lab-grown liver models (called multicellular organoids) that can closely mimic real liver tissue.
We’re taking a broad and detailed approach, studying everything from molecules to full tissue structures. Our work will look at how liver cells respond to damage both from inside the cell (internal factors) and outside the cell (interactions with other cells and the environment), and how these responses lead either to healing or to disease.
In Aim 1, we will look for important parts of the genome—like genes that control cell behavior, signaling pathways, and switches that turn genes on or off—that play a role in liver repair and disease. This will help us understand the big picture of how genes regulate these processes.
In Aim 2, we will study the chemical signals that pass between different types of liver cells, especially between bile duct cells and nearby support cells (called mesenchymal cells). We want to learn how these interactions help the liver heal, and how they might contribute to diseases like liver fibrosis (scarring) when things go wrong.
In Aim 3, we will use this information to build complex 3D liver organoids in the lab. These models will include many different types of liver cells arranged to mimic the natural structure and function of the liver.
Our main goal is to uncover the key molecular and cellular processes that control how the liver regenerates after damage. We also want to use this knowledge to build more advanced lab-grown liver models (called multicellular organoids) that can closely mimic real liver tissue.
We’re taking a broad and detailed approach, studying everything from molecules to full tissue structures. Our work will look at how liver cells respond to damage both from inside the cell (internal factors) and outside the cell (interactions with other cells and the environment), and how these responses lead either to healing or to disease.
In Aim 1, we will look for important parts of the genome—like genes that control cell behavior, signaling pathways, and switches that turn genes on or off—that play a role in liver repair and disease. This will help us understand the big picture of how genes regulate these processes.
In Aim 2, we will study the chemical signals that pass between different types of liver cells, especially between bile duct cells and nearby support cells (called mesenchymal cells). We want to learn how these interactions help the liver heal, and how they might contribute to diseases like liver fibrosis (scarring) when things go wrong.
In Aim 3, we will use this information to build complex 3D liver organoids in the lab. These models will include many different types of liver cells arranged to mimic the natural structure and function of the liver.
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.
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.
By gaining a deep understanding of how liver tissue repairs itself—and how this process can break down—we hope to reveal new insights into liver biology. Creating realistic lab models of the liver will also give us powerful tools to study how the liver maintains its health, heals after injury, or develops disease. Ultimately, applying this work to human cells will help us answer important questions about which parts of the liver’s repair system are shared with other animals and which are unique to humans.