U-M researchers identify of new type of ‘disease-associated’ liver cells, with the potential to protect against MASH
A newly discovered type of liver cells may hold clues for treating severe liver disease, according to a recent study from the University of Michigan Life Sciences Institute.
The findings, published May 1 in the Journal of Clinical Investigation, reveal a signaling pathway that can protect against metabolic dysfunction-associated steatohepatitis (MASH). This more severe form of metabolic-dysfunction associated steatitis liver disease (MASLD) affects 5% to 10% of the U.S. adult population and leads to cirrhosis and liver cancer.
The liver is composed of more than a dozen different cell types, including both liver cells (or hepatocytes) and other cells such as stromal and immune cells. Researchers in the lab of LSI faculty member Jiandie Lin, Ph.D., study the ways these various cell types communicate and interact to maintain a healthy liver environment and how communications change in disease.
Recently, the team analyzed gene expression signatures from individual hepatocytes in both healthy and MASH liver samples to identify specific liver cell types that could point to disease risk.
“Traditionally, hepatocytes are divided into three zones based on location-specific gene expression patterns that are tailored to specialized function,” explains Lin, senior author of the new JCI study. “What was a little bit surprising when we analyzed the data is that, in addition to these three groups of hepatocytes, we found a new cluster of cells with a unique identity. And that particular group of cells only showed up in the MASH liver.”
A prominent feature that differentiated these cells from other hepatocytes was that they displayed signatures of cellular senescence, a stalled state in which the cell no longer divides but also does not die. In this arrested state, senescent cells interfere with normal tissue function, increase harmful inflammation and contribute to disease.
It’s pretty exciting, because only a couple of other studies have identified this cell population, and not much was really known about what these cells are doing in disease.
Further analysis revealed unusual activity from a gene called Themis. This gene, which encodes the protein THEMIS, is typically expressed in a type of immune cells called T cells but is not active in healthy hepatocytes.
“But in both mouse and human MASH liver, Themis expression was strongly increased. It actually ranked as one of the top genes being activated,” says Lin, who is also a professor of cell and developmental biology in the U-M Medical School. “So, the next question is: Is it good or bad? Is this increased THEMIS damaging the liver, or is the cell activating this pathway to help adapt to metabolic stress in MASH?”
To answer this question, the researchers compared liver health in normal mice with that of mouse models in which Themis was deleted specifically from hepatocytes. The livers with no THEMIS fared much worse, showing greater signs of liver injury, senescence, inflammation and fibrosis. Conversely, when THEMIS levels were increased in hepatocytes, the team observed decreased senescence and improved protection from liver injury and MASH.
“It’s pretty exciting, because only a couple of other studies have identified this cell population, and not much was really known about what these cells are doing in disease,” says the study’s lead author Xiaoxue Qiu, Ph.D., a former researcher in the Lin lab who recently started her own lab at the University of Minnesota. “And now we are seeing that Themis is a key regulator of hepatocyte senescence and that manipulating this subtype of disease-associated hepatocytes can have a major impact on disease progression.”
Lin believes the findings offer a starting point to identify additional drivers of liver damage and determine whether the THEMIS pathway can offer a therapeutic target for MASH.
Top image: Illustration of a liver bisected by the scales of justice, often associated with the Greek goddess Themis. Researchers found that mouse livers lacking the protein THEMIS showed greater liver injury and inflammation (left side), while increased THEMIS led to improved protection from liver injury and MASH (right side). Illustration by Rajani Arora, U-M Life Sciences.
"THEMIS attenuates MASH by suppressing disease-associated hepatocyte induction and hepatocyte senescence in mice," Journal of Clinical Investigation. DOI: 10.1172/JCI199303.