Secret boss of the liver: Star-shaped cells that promote fibrosis also regulate liver health

The discovery could be especially important for hundreds of millions of people, including one-third of American adults who have metabolic liver disease. As the metabolic hub of our body, impaired liver function can predispose to liver and cardiovascular disease.

"Our research shows a surprising role for stellate cells in the normal liver, where they act like "secrete bosses," organizing its structure and instructing the work of other cells that perform the liver's main functions, namely metabolism and detoxification," says study leader Robert F. Schwabe, MD, professor of medicine and director of the Digestive and Liver Disease Research Center at Columbia University Vagelos College of Physicians and Surgeons. "But the cells lose these protective functions as liver disease progresses, turning from good into bad guys.

"If we can reprogram diseased stellate cells back to their healthy state, we could potentially halt liver scarring and simultaneously improve liver function, which may be most helpful for patients in advanced disease stages who are not helped by current therapies," adds Schwabe.

The findings were published online in Nature.

What the study found

In the past 40 years, research on the liver's stellate cells has focused on their role in driving diseases that scar the liver. "Evolutionary pressure ensures that we do not have cells in our bodies that only do bad things," Schwabe says. "Every cell must serve some purpose. We were puzzled that the beneficial functions of stellate cells have not been really understood."

To understand the normal functions of the stellate cells in a healthy liver, the researchers genetically engineered mice to eliminate most stellate cells. In these mice, the researchers found that the liver became smaller, disorganized, and had trouble healing injuries, detoxifying drugs, and regulating the liver's metabolism.

Eliminating a single molecule inside the stellate cells -- called RSPO3 -- triggered the same changes as removing stellate cells entirely, including a reduction in liver size, disorganization, an inability to detoxify certain substances and regenerate. Moreover, RSPO3 was found to protect from metabolic dysfunction-associated liver disease (MASLD) and alcohol-associated liver disease in mice.

The researchers also found that in patients with metabolic or alcohol-associated liver disease, the two most common forms of fatty liver disease, declining levels of RSPO3 were associated with worsened disease, suggesting that RSPO3 plays a similar role in people.

Why it matters

The number of people with metabolic liver disease is rapidly increasing, and the disease is poised to become the most common reason for liver transplantation and liver cancer in the U.S.

Restoring stellate cells to their healthy and protective state represents a conceptually new therapeutic approach to liver disease that could simultaneously reduce liver scarring and improve liver function.

"A key problem in patients with metabolic liver disease is that today's drugs only target the metabolic alterations," Schwabe says, "but this approach is less effective in advanced disease stages, where scarring dominates."

What's next

Restoring stellate cell balance could increase the RSPO3 levels in patients and potentially help the liver regain their normal functions and restore metabolism, reduce fibrosis, and heal the liver.

The Columbia researchers are now looking for ways to increase RSPO3 and exploring other avenues for restoring stellate cells to their healthy state.