News from the University of Pennsylvania reports a new method that involves the use of fat to help heal skin without the formation of scar tissue. This work comes from the Perelman School of Medicine at the University of Pennsylvania, and it is the result of a large-scale, multi-year study that collaborated with the Plikus Laboratory for Developmental and Regenerative Biology at the University of California, Irvine. Their findings were published online in the journal Science on January 5th, 2017.
A fancy name for fat is “adipose tissue.” Adipose tissue is actually a rather complicated pastiche of different cell types. Specialized cells in adipose tissue that stores fat are called “adipocytes,” but they are more colloquially called fat cells. Fat cells are normally found in the skin, but when wounds in the skin heal and form, those underlying population of fat cells are lost. In skin tissue that is undergoing the process of healing, the most common cell types are known as “myofibroblasts.” Myofibroblasts are large cells with ruffled membranes, that are kind of a cross between smooth muscle cells and fibroblasts. They have the ability to contract like smooth muscle cells when exposed to molecules that induce smooth muscle to contract, such as angiotensin II or epinephrine. Fibroblasts, which are numerous throughout the skin and other organs, can readily differentiate into myofibroblasts, as can stellate cells found in liver or the pancreas, some smooth muscle cells, progenitor cells in stromal tissue, epithelial cells, or circulating progenitor cells (see B. Hinz, et al, The myofibroblast: one function, multiple origins, Am J Pathol. 2007 Jun;170(6):1807-16). Once it forms, scar tissue also does not properly form any hair follicles and this can give it a rather odd appearance relative to the rest of the skin. The Perelman researchers designed a new strategy to limit scar formation during healing by converting wound-based myofibroblasts into fat cells, which prevents the formation of scarring.
“Essentially, we can manipulate wound healing so that it leads to skin regeneration rather than scarring,” said George Cotsarelis, MD, the chair of the Department of Dermatology and the Milton Bixler Hartzell Professor of Dermatology at Penn, and the principal investigator of this project. “The secret is to regenerate hair follicles first. After that, the fat will regenerate in response to the signals from those follicles.”
Cotsarelis and his colleagues showed that the formation of fat in the skin and hair follicles are separate developmental events, but they are, nevertheless, linked. Hair follicles form first, and the factors required to induce hair follicle formation that are produced by the regenerating hair follicle can also convert surrounding myofibroblasts into fat cells instead of a scar. This underlying fat does not form without the formation of these new hair follicles. These new fat cells are indistinguishable from pre-existing skin-based fat cells that give the healed wound a natural look instead of leaving a scar. Cotsarelis and his gang discovered that a factor secreted by hair follicles called Bone Morphogenetic Protein (BMP) instructs the myofibroblasts to become fat. This single finding represents a tectonic shift on our understanding of myofibroblasts.
“Typically, myofibroblasts were thought to be incapable of becoming a different type of cell,” Cotsarelis said. “But our work shows we have the ability to influence these cells, and that they can be efficiently and stably converted into adipocytes.” This was shown in both the mouse and in human keloid cells grown in culture.
“The findings show we have a window of opportunity after wounding to influence the tissue to regenerate rather than scar,” said the study’s lead author Maksim Plikus, PhD, an assistant professor of Developmental and Cell Biology at the University of California, Irvine. Plikus began this research as a postdoctoral fellow in the Cotsarelis Laboratory at Penn, and the two institutions have continued to collaborate.
These new findings might very well revolutionize dematological wound treatments. These data might be useful for developing therapies that drive myofibroblasts to differentiate into adipocytes that can help wounds heal without scarring.
As Cotsarelis put it: “It’s highly desirable from a clinical standpoint, but right now it’s an unmet need.”
However, wound treatments are not the only use for this work. Fat cell loss is a common complication of other clinical conditions. HIV treatments, cancer, scleroderma, are just a few of the diseases that can cause wasting and drastic weight loss. Also, because fat cells are also lost naturally because of the aging process, especially in the face, which leads to permanent, deep wrinkles, something that available anti-aging treatments cannot satisfactorily address.
“Our findings can potentially move us toward a new strategy to regenerate adipocytes in wrinkled skin, which could lead us to brand new anti-aging treatments,” Cotsarelis said.
The Cotsarelis Lab is now examining how hair follicle regeneration can promote skin regeneration. The Plikus Laboratory would like to know more about the role of BMP in wound healing and are conducting further studies with using human cells and human scar tissue.
Beyond the Dish 