Researchers have been trying to find out how to stop the formation of scars for decades, and now, thanks to a new mouse study, they are one step closer.
Scars are a fast but poor repair
Many of us have scars of one kind or another from accidents or surgery. As unpleasant as they are, the problem of scarring also goes beyond cosmetic concerns. Scar tissue is a poor substitute for healthy skin, as it lacks sweat glands and hair follicles and is structurally weaker and less flexible than skin.
Scarring occurs as an emergency response to injury to rapidly close an opening in the skin. Scar tissue forms much faster than regular skin is able to grow, and so it is chosen as the fastest way to respond to injury and prevent infection or fatal blood loss. Unfortunately, while scar tissue is a fast way to address trauma, it leads to an imperfect repair that can impair normal appearance and function.
In a new study, a team of researchers at Stanford have found out more about why we scar after injury . They have also learned that by interrupting key cell signals during the healing process, wounds can be healed without scarring and are indistinguishable from healthy skin.
The researchers noticed that during skin repair, tension played a key role in the formation of scar tissue. The more tension there is on the wound, the more likely it is that scar tissue will form. A good example of this is when humans are in the fetal stage and scars do not form; this is because fetal skin is jelly-like and lacks the tightness that skin takes on when we are older.
The team showed that by lowering the tension that stretches the wound, the formation of scar tissue is reduced.
Why tension matters in scar formation
Why does tension in the skin around a wound cause scarring in the first place? To answer this, the researchers focused their attention on a gene called Engrailed-1, which facilitates the creation of a specific protein found in fibroblast cells, a type of cell that contributes to scar tissue formation.
They discovered during their experiments that there was a subpopulation of these fibroblasts in the skin that do not express the Engrailed-1 gene normally but begin to do so during the formation of scar tissue.
They then explored how tension might be involved in turning on the Engrailed-1 gene. It has been known for many years that cells can sense their environment, which includes mechanical stresses and tension. Perhaps most interestingly, there are also ways to impair a cell’s ability to sense its environment, and this made the researchers consider doing this to prevent scarring.
Starting with fibroblasts that do not normally express Engrailed-1, the team created three different kinds of environments and allowed the cells to grow in them. There was a culture on a soft gel that created no tension on the growing cells, a culture on a regular plastic dish where there was surface tension, and a culture on the same plastic dish but with a chemical to prevent cells from detecting the presence of tension in the environment.
The results were that cells in the soft gel did not express Engrailed-1, the ones on the plastic dish did, and the ones inhibited from sensing tension also did not express Engrailed-1.
Healing wounds without scarring
This was also confirmed in mice; when tension was applied to healing surgical wounds, there was an increase in the number of cells expressing Engrailed-1 and thus the formation of thicker scar tissue.
Using the drug verteporfin, which is used to treat certain eye conditions and which can block cells from sensing tension and mechanical stress, mice were given anesthesia and surgical incisions were made. Mechanical tension was applied to the wound while administering verteporfin to the healing wound
The results were a mirror of what was seen in the cell experiments. The mouse skin that healed with verteporfin administration looked like normal healthy skin. Indeed, upon examination with a microscope, the skin had normal glands and hair follicles were present in the area of healed skin; normally, this does not happen in scar tissue. The healed skin was structurally as strong as normal skin, and an artificial intelligence algorithm compared many images of healthy skin to the ones healed with verteporfin and could not find any differences.
The next step for the researchers will be further studies in other animals; if successful, a clinical trial will almost certainly follow.
Wounds in adult mammals typically heal by forming fibrotic scars. Mascharak et al. found that a specific population of skin fibroblasts (Engrailed-1 lineage–negative fibroblasts) activate expression of Engrailed-1 and turn on profibrotic cellular programs in response to local tissue mechanics in wounds (see the Perspective by Konieczny and Naik). When mechanical signaling was inhibited in these cells (using either genetic deletion or small-molecule inhibition), skin wounds in mice no longer formed scars but instead healed by regeneration, restoring skin with normal hair follicles and glands, extracellular matrix, and mechanical strength.
This is confirmation that the formation of scar tissue can be prevented, and it opens the door for interventions against other kinds of scarring, such as fibrosis, a common age-related affliction. It may also be possible to combat cardiac scarring after a heart attack. There are also cosmetic applications, and they could spark wider public interest if such a therapy was available after injury or surgical scarring.
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 Mascharak, S., Davitt, M. F., Griffin, M., Borrelli, M. R., Moore, A. L., Chen, K., … & Longaker, M. T. (2021). Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science, 372(6540).
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