Periodic Reporting for period 1 - MacTalk (Adipose tissue-Liver Macrophage CrossTalk in NASH and Fibrosis)
Periodo di rendicontazione: 2022-09-01 al 2025-06-30
Obesity and its related health complications are among the most pressing health challenges in Europe and worldwide. One major complication is metabolic dysfunction–associated steatotic liver disease (MASLD), which affects approximately 25% of the population. MASLD can progress from simple fat accumulation in the liver to chronic liver inflammation and scarring (fibrosis), and in severe cases liver failure or liver cancer. Despite this urgent clinical problem, current treatment options are limited. A key reason is that we still do not fully understand why and how obesity drives liver disease at the cellular level.
Recent findings suggest that immune cells in fat tissue, named adipose tissue macrophages (ATMs), send signals that influence the immune cells, including macrophages, of the liver. In turn, this may determine whether MASLD progresses to more severe disease such as liver fibrosis. However, exactly how ATMs affect liver macrophages, their activation state, and their localization in the liver is unknown. This knowledge gap has limited progress toward targeted therapies.
Our project set out with an ambitious goal: to uncover how adipose tissue macrophages shape liver macrophages and thereby drive liver inflammation and fibrosis. We framed this around two core objectives:
• Objective 1: Define the impact of adipose tissue macrophages on liver macrophage composition and liver fibrosis in MASLD.
• Objective 2: Elucidate how adipose tissue macrophages influence liver macrophage function. Thus, we aimed to pinpoint factors secreted by ATMs that alter macrophage behavior in the liver.
By integrating animal models, cell models and a human translational study, together with advanced immunophenotyping, this project aimed to take a comprehensive approach to this complex problem.
The innovation of this project lies in connecting two tissues, fat and liver, through their immune systems. Understanding this “crosstalk” could open entirely new avenues for treatment to timely stop disease progression. The impact could be substantial, with the potential to influence clinical strategies for millions of people with obesity-related liver disease. By considering sex differences, the project also ensures its results are relevant for gender equality.
Recent findings suggest that immune cells in fat tissue, named adipose tissue macrophages (ATMs), send signals that influence the immune cells, including macrophages, of the liver. In turn, this may determine whether MASLD progresses to more severe disease such as liver fibrosis. However, exactly how ATMs affect liver macrophages, their activation state, and their localization in the liver is unknown. This knowledge gap has limited progress toward targeted therapies.
Our project set out with an ambitious goal: to uncover how adipose tissue macrophages shape liver macrophages and thereby drive liver inflammation and fibrosis. We framed this around two core objectives:
• Objective 1: Define the impact of adipose tissue macrophages on liver macrophage composition and liver fibrosis in MASLD.
• Objective 2: Elucidate how adipose tissue macrophages influence liver macrophage function. Thus, we aimed to pinpoint factors secreted by ATMs that alter macrophage behavior in the liver.
By integrating animal models, cell models and a human translational study, together with advanced immunophenotyping, this project aimed to take a comprehensive approach to this complex problem.
The innovation of this project lies in connecting two tissues, fat and liver, through their immune systems. Understanding this “crosstalk” could open entirely new avenues for treatment to timely stop disease progression. The impact could be substantial, with the potential to influence clinical strategies for millions of people with obesity-related liver disease. By considering sex differences, the project also ensures its results are relevant for gender equality.
In this project we built and optimized an analysis method called spectral flow cytometry. This method allows us to study immune cells in liver tissue in great detail, even though liver tissue is normally very difficult to analyze because it gives off a lot of background signals. By overcoming these technical hurdles, we can now accurately detect and quantify multiple immune cells simultaneously, providing a much more detailed view of the liver immune landscape than previously possible.
Using this method, we carried out a study in mice with MASLD. We looked carefully at how the disease develops over time and how it differs between males and females, something that had not been studied in detail before. This gained novel insights in sex differences in MASLD. These results also helped us to design the next steps in our experiments.
We also started transplantation experiments, moving fat tissue from a group of obese mice to another group of mice with MASLD, to see how immune cells from obese fat tissue influence inflammation and fibrosis in the liver. These experiments are underway.
At the same time, we are studying fat and liver samples obtained from people undergoing abdominal surgery, where we can directly compare fat tissue and liver samples from the same person. This will help us see if what we find in mice also happens in humans.
Finally, we ran cell experiments with fat tissue from obese mice to find out how signals from this obese fat tissue influence immune cells in the liver. These studies have already revealed that obese fat tissue can steer macrophage phenotype and revealed a possible signal molecule that might drive changes in macrophages in the liver. Together, these achievements provide new tools and knowledge that bring us closer to understanding how fat tissue and liver communicate with each other. This understanding could help in developing new treatments to prevent or slow down liver disease.
Using this method, we carried out a study in mice with MASLD. We looked carefully at how the disease develops over time and how it differs between males and females, something that had not been studied in detail before. This gained novel insights in sex differences in MASLD. These results also helped us to design the next steps in our experiments.
We also started transplantation experiments, moving fat tissue from a group of obese mice to another group of mice with MASLD, to see how immune cells from obese fat tissue influence inflammation and fibrosis in the liver. These experiments are underway.
At the same time, we are studying fat and liver samples obtained from people undergoing abdominal surgery, where we can directly compare fat tissue and liver samples from the same person. This will help us see if what we find in mice also happens in humans.
Finally, we ran cell experiments with fat tissue from obese mice to find out how signals from this obese fat tissue influence immune cells in the liver. These studies have already revealed that obese fat tissue can steer macrophage phenotype and revealed a possible signal molecule that might drive changes in macrophages in the liver. Together, these achievements provide new tools and knowledge that bring us closer to understanding how fat tissue and liver communicate with each other. This understanding could help in developing new treatments to prevent or slow down liver disease.
This project has delivered several important advances. First, we developed a new spectral flow cytometry method that works reliably in liver tissue, despite the high background signal (autofluorescence) that normally makes such analysis very difficult. This methodological advance will be valuable to many research groups studying liver disease and can be readily adapted for other autofluorescent tissues.
Second, we gained new insights into how immune cells in fat tissue influence inflammation and fibrosis in the liver. In our mouse studies, we discovered that this process develops differently over time in males and females, an aspect that had been largely unexplored. These findings will help researchers design and interpret experimental models more accurately.
Through fat tissue transplantation experiments, we are determining whether immune cells from unhealthy fat tissue can actively reprogram liver immune cells and drive scarring processes. Complementary ex vivo cell experiments have already demonstrated that fat tissue can alter macrophage phenotype, and we have identified a promising candidate molecule involved in this crosstalk for further investigation. In parallel, our ongoing human study using paired fat and liver biopsies aims to confirm whether similar mechanisms occur in patients. These findings open new opportunities for developing treatments that target immune cells to slow down or stop liver scarring, which is still a major unmet medical need.
To build on these results, further research is needed to confirm the key molecules involved and to test possible interventions in both animal models and human tissues.
Second, we gained new insights into how immune cells in fat tissue influence inflammation and fibrosis in the liver. In our mouse studies, we discovered that this process develops differently over time in males and females, an aspect that had been largely unexplored. These findings will help researchers design and interpret experimental models more accurately.
Through fat tissue transplantation experiments, we are determining whether immune cells from unhealthy fat tissue can actively reprogram liver immune cells and drive scarring processes. Complementary ex vivo cell experiments have already demonstrated that fat tissue can alter macrophage phenotype, and we have identified a promising candidate molecule involved in this crosstalk for further investigation. In parallel, our ongoing human study using paired fat and liver biopsies aims to confirm whether similar mechanisms occur in patients. These findings open new opportunities for developing treatments that target immune cells to slow down or stop liver scarring, which is still a major unmet medical need.
To build on these results, further research is needed to confirm the key molecules involved and to test possible interventions in both animal models and human tissues.