An overgrowth of connective tissue (purple) characterizes fibrosis, shown here in the liver.

SPL/Science Source

Pushing cells to self-destruct combats deadly fibrosis

Each year, millions of people suffer life-threatening scarring in their lungs, heart, and other organs. Doctors have few tools to combat this fibrosis, other than an organ transplant. Now, new research offers clues for how to selectively destroy the cells known as myofibroblasts that drive the condition. In mice, this appeared to halt or even reverse fibrosis’s damaging effects.

The research is preliminary, but it gets to the root of an often intractable condition, says John Varga, a rheumatologist at Northwestern University in Chicago, Illinois, who was not involved in the work. “This idea of selectively killing [myofibroblasts] is extremely appealing.”

In healthy people, myofibroblasts self-destruct after they finish repairing damaged tissue. But sometimes, they don’t respond to the “self-destruct” signal and keep working away when they’re not supposed to. This leads to areas of scarring caused by a buildup of stiff connective tissue, and it can prevent organs from working properly.  

In the new study, the scientists homed in on one of the most dramatic examples of a fibrotic disease, the autoimmune condition scleroderma. In the condition, skin slowly hardens and tightens, and the illness can progress to internal organs like the lungs. In the most heartbreaking cases, “your whole gas exchange is messed up, [and] you suffocate to death,” says Boris Hinz, a cell biologist who studies fibrosis at the University of Toronto in Canada.

The new study’s senior author, physician Andrew Tager, spent years researching lung fibrosis at Massachusetts General Hospital (MGH) in Boston, but died of pancreatic cancer last summer. His former mentee who spearheaded the project, MGH tissue regeneration specialist David Lagares, shepherded the work through publication.

Along with colleagues, the pair focused on a core challenge: how to coax myofibroblasts to self-destruct, a cellular process called apoptosis. Intriguingly, they found that in the activated myofibroblasts driving scleroderma, the mitochondria—the powerhouses of the cell—are loaded with an apoptosis-triggering protein called BIM. And yet, the cells don’t die. “They are primed for death but for some reason don’t execute this program,” Lagares says.

Based on earlier work by their group and others, the researchers eyed a family of proteins called BCL-2. These proteins can both induce or prevent apoptosis, and the team suspected that the balance between these proteins was disrupted in the overactive myofibroblasts. Gene profiling of cells from scleroderma mouse models backed this up. In particular, a protein in that family, Bcl-xL, stops apoptosis and was ramped up in the myofibroblasts. If only they could knock down Bcl-xL, the researchers reasoned, the cells might then self-destruct.

As it happened, a drug compound called ABT-263, or navitoclax, which is now in clinical trials for various types of cancer, did exactly that. Giving affected mice this drug wiped out the damaging myofibroblasts. It also seemed to target the cells selectively, because only myofibroblasts, which travel to the scene of an injury, were expressing lots of Bcl-xL. The drug appeared not just to halt, but to reverse the effects of fibrosis, the team reports today in Science Translational Medicine. The stiff, scarred tissue seemed to “melt,” Lagares says, though exactly how and why that happened still isn’t clear.

These experiments spawned new questions. Among them is whether the specific protein culprit, Bcl-xL, is a problem in people with scleroderma, not just mice. And, if so, is it acting alone? Analysis of fibrotic skin samples from six people hints that there are different antiapoptotic proteins that are keeping the offending myofibroblasts alive. In three people, analysis of cells in the lab pointed to Bcl-xL. But in three others, a different protein, or a combination of two, was suspect.

“They figured out which apoptotic pathways are involved,” Hinz says. And though he’s doubtful that just one drug can do the job, the strategy tested here has “a lot of potential for clinical intervention.” In part that’s because, along with navitoclax, a leukemia drug called venetoclax that blocks a different BCL-2 molecule is also available.

Varga, who cares for patients with scleroderma, welcomes the idea of “precision medicine” to assign different treatment to patients depending on the molecular drivers of their fibrosis. That’s “very cool,” he says, though he stresses that more work is needed to back up these early results.

Lagares is pressing for that now, trying to gather more skin biopsies from scleroderma patients. And, he says, a lot more study is needed to understand what happens when myofibroblasts are wiped out of the damaged tissue. “Are we inducing regeneration of the tissue, healing?” he wonders. “We don’t know exactly what happens.”