Researchers at ISCRM are studying the biological mechanisms of scarring and learning to control it for therapeutic benefit

On a lazy summer day, a child crashes her bike and sustains a surface wound – perhaps a nasty gash on her lower leg that may require a few stiches. Not far away, an older man suffers a non-fatal heart attack, an internal trauma that will have less visible, but more profound implications. The gravity is quite different, but what happens next is not.

Fibrotic scarring tissue (stained green) in a failing heart. ISCRM researchers are learning to control the scarring process to someday improve outcomes for heart attack patients. Photo by Danny El-Nachef PhD

Immediately, the cells surrounding each injury, sensing trouble, signal first-responder cells known as fibroblasts to secret collagen, a protein that forms a matrix of rebuilt tissue. The laceration on the leg will close, promoting healing and preventing infection. The heart, though severely weakened, will remain intact.

The biological process at work in each case is known commonly as scarring – a vital, but often imperfect replacement for any tissue lost to injury.  As a starting point, the examples above illustrate two important factors related to scarring – essentially, timing and location.

First, younger people naturally heal more quickly and completely. Second, some parts of the body, like skin, where stem cells are abundant, have high regenerative capacity.  Other parts, like the heart, where stem cells are scarce or non-existent, hardly regenerate at all.  Where there is less tissue regeneration, there is more scarring, which makes the behavior of fibroblasts critically important.

For decades, researchers have explored the possibility of building a more perfect scar, an intervention that might not change how an otherwise healthy girl recovers from a routine spill, but could revolutionize treatment for many of our leading causes of death, including heart disease.

Jennifer Davis, PhD, Assistant Professor of Bioengineering and Pathology, and a faculty member of the Institute for Stem Cell and Regenerative Medicine (ISCRM) has been studying the basic mechanisms of scarring for more than a decade. Her lab was part of the first research team to map the molecular signaling network that regulates fibroblasts, the cells that secrete scar tissue.

Jennifer Davis, PhD

Today, the Davis lab continues to make discoveries that are helping scientists understand how this critical biological process works, and how to control it for human health. When scar tissue replaces muscle tissue after a heart attack, for example, the heart’s capacity to contract and relax is significantly reduced, limiting blood flow to the rest of the body – the beginning of heart disease. Controlling the process of scarring, and identifying therapeutic pathways, could lead to more complete recovery for heart attack victims, more effective healing for people who suffer from poor wound closure, and better outcomes for patients with certain forms of liver and lung diseases.

“Our approach is to go straight at the source,” says Davis.  “We want to limit the amount of scarring that happens after an injury by modulating the genetic factors that determine the way fibroblasts function.”

In previous work in mice, including a scan of more than 18,000 genes, Davis and Jeff Molkentin, PhD, now Executive Co-Director, Heart Institute and Director, Molecular Cardiovascular Biology at Cincinnati Children’s, opened up new possibilities in scarring research by mapping the gene network in a cardiac fibroblast.

More recently, Davis has teamed up with ISCRM colleague Cole DeForest, PhD, Assistant Professor in Chemical Engineering and Bioengineering, to go one step further – to control that network responsible for scarring.

“Cole’s expertise in biomaterials allows us to create a synthetic environment to study how fibroblasts really work,” explains Davis. “It’s a model to ask fundamental questions about how our body heals.  How does tissue respond during the scarring process? How are other cells affected? What are the genes that control different aspects of scarring? And what are the design specifications to engineer the optimal scar?”

What would designer scarring look like as treatment?  “Translation to patient care would mean finding a druggable pathway in which we would use the right molecule to target the genes specifically in fibroblasts,” says Davis. “Targeting the fibroblast is a major challenge, but we believe that is the key to controlling scar formation.”

Scar-forming fibroblasts indicated by arrows.

In the heart, for example, this could mean reducing the overall amount of scarring, and preserving more muscle tissue that allows the heart to contract and relax – the continuous movements that pump life-sustaining blood throughout the body. Engineering a better scar could also enable more effective cell signaling, allowing the heart to maintain a healthy, steady rhythm.

Better scarring would also benefit patients with pulmonary fibrosis, in which lung tissue becomes damaged, liver fibrosis, or diabetes-related skin and appendage complications. Scarring therapy could even involve a patch treated with a drug that speeds up the closure of major wounds.

For the Davis Lab, learning to build a better scar is a nonstop pursuit. One paper on the horizon will examine how the architecture of collagen fibers in scars inhibits or promotes the signaling and growth of surrounding muscle cells. Another will focus on methods for turning back the clock on fibroblasts to induce better repair after a heart attack.

At the root of every investigation, says Davis, is a commitment to basic discovery research, which often means asking big questions with little preliminary data, in other words, the kind of research not easily funded by NIH, but essential for advances in medicine.  Indeed, Davis is energized by the prospects of future breakthroughs. “With the right investments in our lab, we could expand the discovery work we’re doing already and accelerate how quickly it becomes translational.  It’s an opportunity to support something really exciting.