More than 100 million people in the United States have metabolic dysfunction-associated steatotic liver disease (MASLD), which is marked by fat accumulation in the liver and can progress to more severe conditions involving inflammation and fibrosis.
A team of engineers at MIT has developed a new tissue model that closely replicates the structure of the human liver, including blood vessels and immune cells. According to findings published in Nature Communications, this model can reproduce both inflammation and metabolic dysfunction seen during early stages of liver disease. The researchers say such a system could be used to identify and test potential new drugs for these conditions.
The work is part of ongoing efforts by this group to use microphysiological systems—tissue models that simulate aspects of human organ biology—to study diseases that are difficult to replicate in animal models like mice.
In earlier research, detailed in a January 14 paper in Communications Biology, the team used a previous version of their liver tissue model to study how the drug resmetirom affects liver function. Resmetirom is prescribed for metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of fatty liver disease, but it only works for about 30 percent of patients. The MIT researchers found that resmetirom may trigger an inflammatory response in liver tissue, which could explain its limited effectiveness.
"There are already tissue models that can make good preclinical predictions of liver toxicity for certain drugs, but we really need to better model disease states, because now we want to identify drug targets, we want to validate targets. We want to look at whether a particular drug may be more useful early or later in the disease," said Linda Griffith, School of Engineering Professor of Teaching Innovation at MIT and senior author on both studies.
Dominick Hellen, formerly a postdoctoral researcher at MIT, led the resmetirom study. Erin Tevonian PhD '25 and PhD candidate Ellen Kan were lead authors on the Nature Communications paper describing the new microphysiological system.
Griffith’s laboratory worked with a device called LiverChip—a microfluidic platform she first developed in the 1990s—for their earlier research. This chip allows growth of three-dimensional human liver tissue from hepatocytes (the main cell type found in livers). It is widely used by pharmaceutical companies during drug development since most medications are processed by the liver.
To adapt this technology for MASLD research, Griffith's team modified LiverChip so it could mimic features specific to fatty-liver-related diseases. They simulated MASLD by exposing lab-grown tissue to high levels of insulin along with excess glucose and fatty acids. This resulted in fat buildup and insulin resistance—conditions common among MASLD patients that can eventually lead to type 2 diabetes.
After establishing this model, they treated it with resmetirom—a thyroid hormone mimic meant to break down fat—and observed increased immune signaling and markers indicating inflammation.
"Because resmetirom is primarily intended to reduce hepatic fibrosis in MASH, we found the result quite paradoxical," said Hellen. "We suspect this finding may help clinicians and scientists alike understand why only a subset of patients respond positively to the thyromimetic drug. However, additional experiments are needed to further elucidate the underlying mechanism."
The newer chip described in Nature Communications goes further by allowing blood vessels and immune cells within engineered tissue. This advance lets researchers observe how vascular networks form through growing tissue as well as track immune cell movement under different health conditions—including those mimicking type two diabetes versus healthy states.
"Making more sophisticated models of liver that incorporate features of vascularity and immune cell trafficking that can be maintained over a long time in culture is very valuable," Griffith said. "The real advance here was showing that we could get an intimate microvascular network through liver tissue and that we could circulate immune cells. This helped us to establish differences between how immune cells interact with the liver cells in a type two diabetes state and a healthy state."
As they matured their engineered tissues using higher levels of insulin, glucose, and fatty acids—the hallmarks leading up to insulin resistance—the team noted changes similar to those seen clinically: reduced capacity for clearing insulin or metabolizing glucose; narrowing or leaking blood vessels associated with diabetic complications; increased inflammation attracting monocytes (precursors for macrophages involved both with repair during inflammation as well as early-stage human disease).
"This really shows that we can model the immune features of a disease like MASLD, in a way that is all based on human cells," Griffith said.
Funding sources included grants from federal agencies such as NIH as well as support from NovoNordisk, Massachusetts Life Sciences Center, Siebel Scholars Foundation, and NSF Graduate Research Fellowships.
