Scars are often the unwanted and permanent result of wound healing. But University of California, Irvine, and University of Pennsylvania researchers have discovered a natural regeneration process that they say stimulates scar-free skin repair.

The study results, which appear in Science, may point the way toward possible clinical treatments for scar-free wound healing.

New fat cells regenerate in the center of the wound from myofibroblasts, principal scar cells, in blue.New fat cells regenerate in the center of the wound from myofibroblasts, principal scar cells, in blue.UCI’s Maksim Plikus, Penn’s Dr. George Cotsarelis and their colleagues identified in mouse studies cellular and molecular processes in which large wounds in adult mice regenerated nearly normal-looking skin, complete with new hair follicles and fat tissue. Ultimately, the center of the wound became nearly indistinguishable from normal, unwounded skin.

Christian F. Guerrero-Juarez, a graduate student in Plikus’ lab, says that, typically, myofibroblasts, the primary cell type found in wounds, were thought to be incapable of becoming other cell types. However, the team found that wound myofibroblasts can convert into new distinct cell types, specifically new adipocytes, which are the fat-laden cells necessary for healthy skin.

Guerrero-Juarez says the study established that wounds with hair follicles produce the instructive factors that can reprogram myofibroblasts into adipocytes. Critical for driving the rewiring of cells’ identity is bone morphogenic protein signaling. In skin wounds, hair follicles secrete large amounts of these BMP molecules. The fact that hair follicles act as the natural source of BMPs explains why hairless wounds cannot regenerate adipocytes.

According to the research, wound healing can be manipulated so that it leads to skin regeneration rather than scarring. The secret is to regenerate hair follicles first. After that, the fat will regenerate in response to the signals from those follicles.

Plikus, an assistant professor of developmental and cell biology at UCI, says that in culture conditions, exposure of human fibroblasts derived from keloids, a type of skin scar, to either pure BMP or to human hair follicles is sufficient to drive their reprogramming toward new adipocytes. This shows that the study’s findings from mice are translatable to humans.

He says that regenerating fat cells in skin can be beneficial for conditions beyond scarring. The process could potentially become a new anti-aging treatment, as the formation of deep wrinkles is thought to result from permanent loss of skin fat.

Without underlying fat, the skin’s surface shrinks and wrinkles like a deflating balloon. Another recent study in Science, to which Plikus’ lab contributed, showed that, beyond their cosmetic value, fat cells possess strong antimicrobial properties that help skin fend off infection.

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