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.
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.
Learning to Control Scarring
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?”
Designer Scarring to Treat Disease and Heal Wounds
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.”
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. In September, research shedding new light on the relationship between collagen structure and fibroblast phenotype was published in the journal Circulation Research. The study was authored by ISCRM PhD students Darrian Bugg, Ross Bretherton, and Emily Olszewski, along with former ISCRM trainee Peter Kim, and conducted in partnership with the Stevens Lab, DeForest Lab, and former ISCRM faculty member Deok-Ho Kim. In the investigation, the researchers used biomimicry techniques to compare different alignments of collagen in the “border zone” of a mouse heart (where muscle abuts scar) and found that spatial factors played an important role in cell behavior. The findings suggest new possibilities for spatially targeted therapy, including a particular molecule involved in controlling scarring. “We saw a positive feedback loop,” says Davis. “Cells get turned on to make a scar, but based on where they are located, they might stay turned on indefinitely because the scar signal is always there, even when it should have stopped. It’s another avenue to potentially controlling the scarring process for better recovery.”
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.”
In the meantime, Davis will be expanding her role in the UW heart research community. Recently, she was named the new director of the Center for Cardiovascular Biology. This important ISCRM research partner, established in 2003, is based at UW Medicine South Lake Union, and comprises 24 faculty members, multiple core labs and more than 30,000 square feet of research space. Jen will be helping to advance the center’s mission of discovering the molecular basis of cardiovascular disease, harnessing this information to develop new therapies, and training the next generation of cardiovascular physicians and scientists.