- Dilated Cardiomyopathy (DCM), a leading cause of heart failure, has long been seen as a problem rooted in defective muscle cells. But the heart is more than muscle—it’s a complex system of interacting cell types.
- Now, in a paper in Science, a multidisciplinary UW research team of biologists, engineers, and physicians shows that fibroblasts, often thought of as helpers, may weaken the heart by causing a harmful cycle of stiffening and scarring.
- In a key finding with potential clinical implications, the team demonstrates that shutting down a signaling pathway in the rogue responder cells restored heart functioning.
- The study showcases a multidisciplinary, collaborative approach and an ability to develop new experimental models and techniques to uncover fundamental disease mechanisms.
Dilated cardiomyopathy (DCM), a condition in which the heart weakens and struggles to pump efficiently, affects roughly 1 in 250 people worldwide, making it one of the most common inherited causes of heart failure. In the United States alone, it’s estimated that at least 750,000 individuals live with the disease.
Not surprisingly, researchers have spent decades studying the cells and the subcellular machinery that generate the pumping power our hearts need to send life-sustaining blood, oxygen, and nutrients throughout our bodies. Although there have been gains in understanding, effective treatments remain elusive.
Nearly a decade ago, a team of investigators at the University of Washington began to look more closely at another resident cell in the heart – fibroblasts. Under normal circumstances, these supporter cells help with ongoing cardiovascular maintenance. When the heart is injured or threatened, however, fibroblasts spring into action. Their mission is to repair damaged tissue by secreting proteins that make up the extracellular matrix (primarily collagen) – essentially a scar created to keep the heart intact.
This scarring – or fibrosis – has traditionally been viewed by researchers and physicians as a side effect of conditions like DCM, rather than a main driver of disease. Now, a script-flipping study from the UW researchers and their colleagues reveals that fibroblasts are not just doing routine damage control – they are actively contributing to the problem.
In a particularly exciting discovery, the team showed that when they shut down a signaling pathway known to promote fibrosis, they were able to curtail further damage to the heart, suggesting they may have pinpointed a therapeutic target.
The findings are detailed in a paper published this week in Science.
The senior author of the study is Jen Davis, PhD, an Associate Professor of Bioengineering and Lab Medicine and Pathology and the Interim Director of the Institute for Stem Cell and Regenerative Medicine (ISCRM). ISCRM faculty members Mike Regnier, PhD, Farid Moussavi-Harami, MD, Nate Sniadecki, PhD, and Cole DeForest, PhD are also authors. The co-first authors of the paper are Ross Bretherton, PhD, a former graduate co-mentored by Dr. Davis and Dr. DeForest, and Bella Reichardt, PhD, who recently completed her doctorate in the Davis Lab.
Holding the Heart Together: A Multiscale Look at a Multifactor Problem
In the investigation, researchers in the Davis Lab genetically engineered heart muscle cells in mice to express a mutation associated with DCM. This “in vivo” approach allowed the investigators to view the interplay between all of the biological components involved in fibrosis, (including the muscle cells, fibroblasts, and extracellular matrix) and the mechanical cues emanating from the expansion and contraction of the heart.
Additional experiments in the Cell Biomechanics Lab (led by Dr. Sniadecki) and the DeForest Research Group played an equally important role in the study. Having seen the process unfold in a living system, the researchers wanted to deconstruct the big picture into pieces. Using tools like engineered heart tissues and synthetic hydrogels that gave them precise control over the cellular environment, the team was able to validate the mouse experiments and to better understand the mechanical signals that were triggering the harmful fibrotic response.
“We saw that the otherwise normal fibroblasts were not simply secreting extracellular matrix proteins like they do in almost all other disease settings,” explains Davis. “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.”
“We could see the pattern clearly,” adds Dr. 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 – and it just kept looping in a vicious cycle.”
Reichardt describes another set of experiments that may have important clinical implications. “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 up 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.”
Making sense of the web of factors at work in runaway fibrosis required powerful analytical technology and expertise. For this, the team turned to Dr. Regnier, who runs his own lab and is the Director of the Center for Translational Muscle Research (CTMR). The Regnier Lab used cutting-edge instrumentation in the CTMR to provide multiscale functional analysis of the biomechanics of fibrosis at the protein, cell, and whole organ levels.
These ISCRM researchers have been studying this phenomenon for nearly a decade. In a 2016 paper published in the journal Cell, Davis, Regnier, and Moussavi-Harami discovered that the amount of contractile tension generated by heart muscle cells over time explains why some inherited genetic mutations in the heart’s contractile machinery cause the heart to thicken while others cause it to stretch and weaken, as in DCM, findings that are foundational for the new paper.
“Ten years down the road, we see once again that the mechanical cues are driving all of the problems,” Davis continues. “When the heart expands, it fills with blood. And we think the fibroblasts are trying to prevent the overexpansion – to not let the balloon pop.”
New Treatment Strategies for Dilated Cardiomyopathy
The insights from the landmark study have the potential to inform new treatment strategies for DCM. Currently, patients are typically prescribed heart failure medications and some have benefitted from drugs that boost the contractile power of proteins (known as myosin) that are a part of the heart’s pumping machinery. While these interventions can help manage symptoms, they do not stop scarring or cure the disease.
According to the researchers, the revelations described in the new paper represent a potential shift in heart research by highlighting the importance of focusing on the entire organ system. “Our data show that just treating the muscle cells is not going to be enough for DCM patients,” says Davis. “It’s essential to target fibroblast, too.”
“Most heart conditions have a fibrotic response that can be harmful,” says Dr. Moussavi-Harami, who sees heart disease patients in his UW Medicine cardiology clinic. “But we actually 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.”
Dr. Moussavi-Harami imagines that someday patients might even be classified by fibrosis level—high, medium, or low—to guide personalized treatments designed by physicians based on an individual’s profile.
Team Science Paints a New Picture
All of the researchers involved agree the study would not have been possible without an established, mission-minded research community capable of contributing expertise in cardiovascular biology, genetics, tissue engineering, biomechanics, and fibrosis.
Davis speaks to the specialized skillsets required for the study. “We had to build engineered heart tissues. We had to use novel biomaterials to understand the mechanics involved in fibrosis. There’s no chemical code to manipulate these dynamics. You actually have to go in and push and pull. And the only way we could do it was through these systems that Cole DeForest and Nate Sniadecki developed.”
Her ISCRM colleagues echo the importance of teamwork for the study.
“Dilated cardiomyopathy is a multifactor problem,” says Dr. Sniadecki. “And it is hard to understand the relationships between multiple factors. The heart is complex. Our goal was to deconstruct the heart and study the pieces, then add them together again to understand how they interact. That’s more than any one lab could ever do alone.”
“This shows what you can do when people with complementary strengths rally around a study that’s more than the sum of the parts,” adds Dr. Regnier. “Collectively, as an Institute, we can do multiscale research. We can look at the myosin molecule, the myofibrils, the cells, and the whole heart. And we can look at different components, including fibroblasts, extracellular matrix, mitochondria, calcium handling, contraction, and the communication between the extracellular matrix and the cardiomyocytes. This paper helps show that we need to do team science, to really get to that next level of understanding and the ability to treat diseases.”
Cole DeForest believes the study further validates emerging modeling techniques, which will become increasingly important as the field continues to reduce its reliance on animals in human disease research.
“Our findings highlight the interplay between advanced animal models and engineered in vitro systems that can provide complementary or additional insights. Looking forward, I believe we’ll point to this as an early example of how you could use these platforms to ask questions that you simply can’t in purely in vivo models.”
Likewise, Davis nods to ongoing experiments that confirm in greater detail how the misunderstood cells once viewed as responders can actually harm the heart in some circumstances, findings that are a part of the new picture taking shape. “We are learning consistently that you cannot look at a single cell type. You have to look at the organ and the organism as a whole. You have to look at all aspects of the heart that have to function correctly together. We can’t just look at one piece of the puzzle anymore.”