Scars are a common aftermath of injuries, surgeries, or burns, often considered merely a cosmetic concern. However, scars can have profound implications beyond their appearance. They can stiffen tissue, restrict movement, affect organ function, and sometimes cause chronic pain.
What surprises many is that internal scarring, known as fibrosis, can be deadly. It’s estimated that about 45% of deaths in the United States are linked to some form of fibrosis, particularly affecting vital organs like the lungs, liver, or heart.
Understanding the Impact of Scarring
Scarring changes how tissue functions. Skin scars, for instance, are not just about aesthetics. Scarred skin is stiffer and weaker compared to normal skin, lacking sweat glands or hair follicles, which makes it challenging for the body to regulate temperature. This can be crucial during a hot day, a fever, or while recovering from a significant injury.
Moreover, scarring doesn’t always remain “neat.” In some individuals, scar tissue can thicken, tighten, or continue to remodel over months. Internally, fibrosis can gradually replace healthy tissue with something tougher and less functional, akin to patching a leak with glue instead of repairing the pipe.
The Unique Healing of Facial Wounds
Doctors have long observed that facial wounds tend to heal with less scarring compared to injuries on other body parts. This phenomenon suggests that the body employs different repair strategies depending on the injury’s location.
“The face is the prime real estate of the body,” said Dr. Michael Longaker. “We need to see and hear and breathe and eat. In contrast, injuries on the body must heal quickly. The resulting scar may not look or function like normal tissue, but you will likely still survive to procreate.”
A new study from Stanford Medicine delves into this observation, offering insights into how the body might be coaxed away from heavy scarring towards genuine repair.
Research Insights from Stanford Medicine
The study suggests that modifying an ancient healing pattern could potentially help people avoid scars after surgery or trauma, and even treat existing scars.
“The face and scalp are developmentally unique,” said Dr. Derrick Wan. “Tissue from the neck up is derived from a type of cell in the early embryo called a neural crest cell.”
In their research, scientists identified specific healing pathways in scar-forming cells known as fibroblasts, originating from the neural crest, which drive a more regenerative type of healing.
Exploring Healing in Different Body Locations
To understand the differences in healing, researchers conducted experiments on lab mice, creating small skin wounds on the face, scalp, back, and abdomen. They ensured the mice were under anesthesia, provided pain relief, and stabilized the wounds to prevent movement from affecting the outcomes.
After 14 days, wounds on the face and scalp showed lower levels of proteins associated with scar formation, resulting in smaller scars. The researchers then transplanted skin from these areas onto the backs of other mice, repeating the wound experiment.
Facial Skin and Reduced Scarring
Remarkably, skin originally from the face continued to exhibit reduced scarring even after transplantation. Injecting fibroblasts from different body sites into mice revealed that facial fibroblasts led to lower levels of scarring-related proteins compared to those from the scalp, back, or abdomen.
“Many of the authors on this paper are fellow physician scientists,” said Dr. Dayan J. Li. “This project was inspired by what we’ve observed in our patients – facial wounds in general heal with less scarring. We wanted to understand, mechanistically, why this is.”
Potential for Future Treatments
One significant finding was the minimal number of cells needed to alter healing. The team discovered that even when altered fibroblasts comprised a small fraction of the total cells near a wound, the healing pattern shifted towards less scarring.
“We found you don’t need to change or manipulate all fibroblasts within the tissue to have a positive outcome,” Li said. “Changing just a few cells can trigger a cascade of events that can cause big changes in healing.”
The scientists traced this effect to a signaling pathway involving a protein called ROBO2, which helps keep facial fibroblasts in a less-fibrotic state. They also found that ROBO2-positive fibroblasts had DNA that was less transcriptionally active, meaning it was less open for proteins to bind and turn genes on.
Existing Drug Targets and Future Implications
The pathway extends beyond ROBO2 to EP300, a protein that aids in gene expression. In fibroblasts prone to scarring, EP300 activity supports gene expression leading to fibrosis. The team discovered that inhibiting EP300 activity using a pre-existing small molecule made back wounds heal more like facial wounds.
“It seems that, in order to scar, the cells must be able to express these pro-fibrotic genes,” Longaker said. “And this is the default pathway for much of the body.”
Given that EP300 is already being studied in cancer research, there are ongoing clinical trials for small molecules that inhibit it. This presents a potential shortcut for developing treatments to improve wound healing.
“Now that we understand this pathway and the implications of the differences among fibroblasts that arise from different types of stem cells, we may be able to improve wound healing after surgeries or trauma,” Wan said.
Dr. Longaker anticipates that these findings could extend beyond skin to internal scarring as well.
“There’s not a million ways to form a scar. This and previous other findings in my lab suggest there are common mechanisms and culprits regardless of the tissue type, and they strongly suggest there is a unifying way to treat or prevent scarring.”
The full study was published in the journal Cell.
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