A Possible Path to Prevent Scarring in Mammals

Scarring occurs in mammals but not in highly regenerative species such as salamanders. Some research results from past years suggest that scar formation isn't an essential part of the mammalian healing process, such as the ability of MRL mice to heal minor wounds without scars. Here researchers report on initial progress towards a potential means of suppressing scar formation:

Scars are comprised mainly of collagen, a fibrous protein secreted by a type of cell found in the skin called a fibroblast. Collagen is one of the main components of the extracellular matrix - a three-dimensional web that supports and stabilizes the cells in the skin. "The biomedical burden of scarring is enormous. About 80 million incisions a year in this country heal with a scar, and that's just on the skin alone. Internal scarring is responsible for many medical conditions, including liver cirrhosis, pulmonary fibrosis, intestinal adhesions and even the damage left behind after a heart attack."

In late 2013, a study showed that fibroblasts in the skin of mice arise as two distinct lineages. One, in the lower layer of the skin, mediates the initial steps of repair in response to wounding. Researchers wondered whether this fibroblast type, which expresses a protein called engrailed, could be responsible for the collagen deposition that leads to scarring. They generated genetically engineered mice in which the cells, called EPF cells for "engrailed-positive fibroblasts," were labeled with green fluorescent protein to allow tracking of the cells' location during the animals' development. The cells were also engineered to carry a "kill switch" that could be activated by the presence of diphtheria toxin, which would allow the researchers to assess how wounds healed in the absence of EPF cells.

The researchers found that the proportion of EPF cells, compared to the overall number of fibroblasts in the skin on the backs of the animals, increased dramatically from less than 1 percent in 10-day-old embryos to about 75 percent in mice that were 1 month old. The researchers also found evidence pointing to a major role for EPF cells in scarring. After diphtheria toxin was applied to wounds on the backs of mice, the wounds healed with less scarring. "The EPF cells are clearly responsible for the vast majority of scarring." Complete healing in the diphtheria-toxin-treated wounds required an additional six days compared to controls, but much of the repaired skin looked and appeared to function normally. In contrast, scarred skin is frequently less flexible and weaker than uninjured skin.

When the researchers analyzed the EPF cells more closely, they found that they express a protein called CD26 on their surface. CD26 activity has been implicated in the metabolism of many hormones, including insulin, and the human version of the protein is a target for inhibitors such as sitagliptin and vildagliptin that are marketed for treating low blood sugar levels in people with type-2 diabetes. The researchers found that a small molecule that blocks the activity of CD26 also reduced the amount of scarring in a manner similar to that seen when EPF cells were eliminated. In particular, scars that formed on wounds treated with the CD26-inhibitor covered an area of only about 5 percent of the original wound. In contrast, untreated skin formed scars that covered over 30 percent of the original wound area.

Link: http://med.stanford.edu/news/all-news/2015/04/cell-type-responsible-for-scarring-skin-cancer-growth-identified.html

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