A groundbreaking development in liver disease research has emerged from the Massachusetts Institute of Technology (MIT), offering a glimmer of hope for the over 100 million people in the United States battling metabolic dysfunction-associated steatotic liver disease (MASLD). This condition, characterized by a dangerous accumulation of fat in the liver, can progress into more severe liver diseases, causing inflammation and fibrosis.
In their quest to find new treatments, MIT engineers have crafted a novel tissue model that faithfully mimics the intricate architecture of the liver, including its blood vessels and immune cells. Published in Nature Communications, the researchers showcase how this model accurately replicates the inflammation and metabolic dysfunction seen in the early stages of liver disease, providing a powerful tool for drug discovery and testing.
This study is part of a larger initiative by the team to explore human liver biology using tissue models, or microphysiological systems, as animal models often fall short in replicating these complex processes. In a previous study, the researchers utilized an earlier version of their liver tissue model to investigate the response to resmetirom, a drug used to treat metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of liver disease. Surprisingly, they found that this drug induced an inflammatory response in liver tissue, potentially explaining its limited effectiveness in only 30% of patients.
"We need to model disease states better because we want to identify drug targets and validate them. We want to understand if a particular drug is more beneficial early or later in the disease progression," explains Linda Griffith, the School of Engineering Professor of Teaching Innovation at MIT and the senior author of both studies.
In the Communications Biology paper, Griffith's lab built upon their original microfluidic device, the LiverChip, which provides a simple scaffold for growing 3D liver tissue models from hepatocytes, the primary cell type in the liver. This chip is widely used by pharmaceutical companies to test for liver toxicity, a critical step in drug development as most drugs are metabolized by the liver.
For the new study, Griffith and her team modified the chip to study MASLD. Patients with MASLD, characterized by fat buildup in the liver, can progress to MASH, a more severe disease marked by the formation of scar tissue (fibrosis) in the liver. Currently, resmetirom and the GLP-1 drug semaglutide are the only FDA-approved medications for treating MASH, highlighting the urgent need for new treatment options.
"You can't declare victory over liver disease with just one drug or class of drugs. Over the long term, there may be patients who can't use them, or they may not be effective for everyone," Griffith emphasizes.
To create a model of MASLD, the researchers exposed the tissue to high levels of insulin, along with large quantities of glucose and fatty acids. This led to the development of fatty tissue and insulin resistance, a common trait in MASLD patients that can progress to type 2 diabetes.
When the researchers treated this model with resmetirom, a drug that mimics the effects of thyroid hormone to break down fat, they were surprised to find an increase in immune signaling and markers of inflammation.
"Since resmetirom is primarily intended to reduce hepatic fibrosis in MASH, we found this result quite paradoxical. We suspect this finding may help clinicians and scientists understand why only a subset of patients respond positively to the thyromimetic drug. However, further experiments are needed to elucidate the underlying mechanism," says Dominick Hellen, the lead author of the resmetirom paper.
In the Nature Communications paper, the researchers introduce a new chip that allows for a more realistic reproduction of the human liver's architecture. The key innovation was developing a method to induce blood vessels to grow into the tissue, enabling the delivery of nutrients and the flow of immune cells.
"Creating more sophisticated liver models that incorporate vascularity and immune cell trafficking, which can be maintained over a long time in culture, is extremely valuable. The real breakthrough here was showing that we could achieve an intimate microvascular network through liver tissue and circulate immune cells. This helped us establish differences between how immune cells interact with liver cells in a type two diabetes state and a healthy state," Griffith explains.
As the liver tissue matured, the researchers induced insulin resistance by exposing it to increased levels of insulin, glucose, and fatty acids. As the disease state progressed, they observed changes in how hepatocytes cleared insulin and metabolized glucose, as well as narrower, leakier blood vessels reflecting microvascular complications often seen in diabetic patients. They also found that insulin resistance led to an increase in inflammatory markers, attracting monocytes into the tissue. Monocytes are precursors to macrophages, immune cells that aid in tissue repair during inflammation and are also observed in the livers of patients with early-stage liver disease.
"This demonstrates that we can model the immune features of a disease like MASLD using human cells," Griffith concludes.
The research was funded by the National Institutes of Health, the National Science Foundation Graduate Research Fellowship program, NovoNordisk, the Massachusetts Life Sciences Center, and the Siebel Scholars Foundation.
