Cells usually viewed as menders may harm the heart

Fibroblasts, cells that repair heart damage, might cause a cycle of stiffening and scarring in certain heart conditions. 

Dilated cardiomyopathy, a leading cause of heart failure, has been seen as rooted in defective heart muscle cells. But the heart is a complex system of interacting cell types.  

A study published Sept. 11 in Science reexamined the role of fibroblasts and found they might be contributing to the disorder. 

“We saw that the otherwise normal fibroblasts were not simply secreting extracellular matrix proteins like they do in almost all other disease settings,” explained senior author Jen Davis, associate professor of bioengineering at University of Washington School of Medicine and UW College of Engineering. “Instead, they were using their own cell bodies to hold the heart together, which caused the organ to stiffen. As the heart weakened and enlarged, they started making excessive amounts of fibrosis.” 

The team demonstrated that shutting down a signaling pathway in the rogue fibroblasts restored heart functioning in laboratory models. That finding could have therapeutic implications.  

In dilated cardiomyopathy, the heart struggles to pump efficiently. The disease affects roughly 1 in 250 people worldwide, making it one of the most common inherited forms of heart failure. Effective treatments remain elusive. 

Nearly a decade ago, UW researchers began studies of how fibroblasts assist with cardiovascular maintenance. When the heart is injured, fibroblasts spring into action. They secrete proteins that create a scar to keep the heart intact.  

This fibrosis was considered a side effect, rather than a main driver, of conditions like dilated cardiomyopathy. The latest research reveals, however, that fibroblasts are not just doing routine damage control, they could be aggravating the problem.  

The Davis Lab at the Institute for Stem Cell and Regenerative Medicine genetically engineered heart muscle cells in mice to express a mutation associated with dilated cardiomyopathy. This approach exposed the interplay among various biological components in fibrosis, including muscle cells, fibroblasts and extracellular matrix, as well as the mechanical cues emanating from expansion and contraction of the heart.  

Several other UW labs — those of Mike Regnier, Farid Moussavi-Harami, Nate Sniadecki, and Cole DeForest —collaborated.  Co-first authors of the paper are Ross Bretherton, a former graduate student co-mentored by Davis and DeForest, and Bella Reichardt, who completed her doctorate in the Davis Lab.  

The Cell Biomechanics Lab used tools like engineered heart tissues and synthetic hydrogels that gave them precise control over the cellular environment.  

“We could see the pattern clearly,” said Reichardt. “We saw the fibroblasts start to remodel the extracellular matrix, we saw the heart become stiffer as a result, and we saw how that fed back into more problems in the muscle cells, which exacerbates the scarring. It just kept looping in a vicious cycle.”  

Reichardt added, “We had another genetically altered mouse in which we could knock out the P38 signaling pathway in the fibroblasts and halt both the expansion of the fibroblast population and the late onset of scar production, which also prevented some of the impairment both in the myocyte and at the whole heart level. This opens the possibility that if doctors were able to intervene at an earlier timepoint, they might be able to prevent some of the loss of function associated with heart disease.”  

At the Center for Translational Muscle Research, Regnier’s team conducted multiscale functional analyses of the biomechanics of fibrosis at the protein, cell, and whole organ levels.  

“We see once again that the mechanical cues are driving all of the problems,” Davis noted, “When the heart expands, it fills with blood. We think the fibroblasts are trying to prevent the overexpansion to not let the balloon pop.”  

Dilated cardiomyopathy patients are typically prescribed heart failure medications. Some benefit from drugs that boost the contractile power of myosin proteins in the heart’s pumping machinery. While these interventions can help manage symptoms, they don’t stop scarring or cure the disease.  

“Our data shows that just treating the muscle cells is not going to be enough for DCM patients,” said Davis. “It’s essential to target fibroblast, too.”  

“Most heart conditions have a fibrotic response that can be harmful,” said UW Medicine cardiologist Dr. Moussavi-Harami. “But we don’t have many therapies to address it. The uniqueness of this study is that we show functional improvement by knocking out the p38 pathway that drives fibrosis. I think that this strategy, in combination with other therapies like myosin activators, could be beneficial for patients who have genetic cardiomyopathies like DCM.”  

Moussavi-Harami imagines that patients might someday be classified by fibrosis level —high, medium or low — to guide personalized treatments.  

News release written by Thatcher Heldring, UW Medicine Institute for Stem Cell and Regenerative Medicine Research.