Researchers at Rutgers University have discovered that a protein produced by an intestinal nematode parasite, Heligmosomoides polygyrus, can be used to enhance wound healing in mice. The study showed that applying the protein, TGF-β mimic (TGM), to skin wounds under a Tegaderm bandage accelerated wound closure, improved skin regeneration, and inhibited the formation of scar tissue. In their published paper in Life Science Alliance, the researchers, led by William C. Gause, PhD, director of the Center for Immunity and Inflammation at Rutgers, commented that the findings from their murine study “… show that topical application of TGM is effective in both enhancing wound healing and generating an overall beneficial long-term outcome for standard wound treatment.”
Their published report is titled “Helminth protein enhances wound healing by inhibiting fibrosis and promoting tissue regeneration.”
Skin is an important barrier and defense mechanism in mammalian hosts, and after an injury the body needs to quickly activate a wound healing response, the authors wrote. “Wound repair is a highly regulated system that clears the injured area of external pathogens and covers the exposed area to prevent further damage and reduce infection.” The tissue repair process involves three main overlapping stages; inflammation, proliferation, and maturation, they continued. During the inflammatory stage multiple cell types are recruited to the wound area immediately after damage. During proliferation endothelial cells, macrophages and fibroblasts covering the wound are activated. The final, maturation stage involves production and deposition of the extracellular matrix. However, rapid wound closure can favor the development of scar tissue instead of properly regenerated skin. “Fibrosis is frequently associated with skin wound repair,” they wrote. “It results in tissue scarring in place of regeneration and is considered a significant public health burden, resulting in billions of dollars spent each year.”
The balance between scarring and successful tissue regeneration is strongly influenced by immune cells recruited to the wound site, the team continued. “After wound closure, the maturation phase of wound healing includes the recruitment and activation of various immune cell populations that can influence whether the healing process favors a pro-fibrotic pathway associated with scarring or a more favorable pro-regenerative pathway.” Many researchers are interested in finding ways to boost the activity of immune cell types that promote regeneration, while inhibiting the activity of immune cells that promote tissue scarring. “The development of a treatment that both rapidly suppresses harmful inflammatory responses and induces the expression of tissue repair factors that favor tissue regeneration over scarring could promote more effective wound healing and lead to better clinical outcomes,” the investigators continued.
Recent studies have suggested that excretory/secretory (ES) molecules expressed by parasitic worms might modulate the host’s immune system in ways that promote tissue regeneration. “One recently discovered ES protein, TGF-β mimic (TGM), binds the TGF-β receptor, though likely has other activities.” The TGF-β receptor is found on the surface of many cell types in mice and humans, including immune cells.
TGM is an ES produced by Heligmosomoides polygyrus, a parasitic roundworm that lives in the intestines of mice and other rodents. Interestingly, the team noted, previous studies had reported that “TGM exerts anti-inflammatory effects in vivo in models of colitis, graft rejection, and airway allergy.”
The recent availability of large quantities of recombinant, highly purified TGM meant that it was possible to carry out further in vivo analyses. For their reported research Gause, together with first author Katherine E. Lothstein, PhD, and colleagues carried out a series of in vitro tests and in vivo studies in mice to assess whether administration of H. polygyrus ES products (HES), and specifically TGM, could promote tissue repair and modulate the progression of skin wound healing. “We administered the recently identified recombinant TGM molecule, originally isolated from helminth ES products, immediately underneath a protective Tegaderm bandage,” they wrote.
Their experiments found that daily topical applications of TGM, combined with use of a Tegaderm bandage, accelerated the closure of skin wounds in mice. Moreover, TGM treatment reduced the formation of scar tissue while enhancing skin regeneration. Unlike untreated animals, TGM-treated mice were able to form new hair follicles within the wounded region of the skin. “… in the TGM treated wounds, there was observed complete sebaceous glands and hair shafts, denoting normal skin development associated with tissue regeneration,” they wrote.
TGM treatment appeared to stimulate the recruitment of immune cells known as macrophages into wounds and reprogram them to promote tissue regeneration. The data, the investigators stated, “… show that TGM alters the macrophage landscape in tissues undergoing wound healing responses. Taken together, these analyses suggest that macrophages induced following TGM treatment generally show a reduced expression of CD206, but up-regulation of many markers associated with M2 macrophages and the wound healing process.”
The team pointed out that as a recombinant product, TGM is easily produced, and can be standardized for treatment in combination with a bio-occlusive bandage, such as Tegaderm. They acknowledged that further research will be needed to investigate whether the protein can be harnessed to enhance wound healing in human patients.
In their discussion, the scientists concluded, “Taken together, these studies provide a significant framework for the potential use of a highly purified helminth ES product as a therapy to promote cutaneous wound healing.” Added Gause, “In this study, we have developed a novel therapy for the treatment of skin wounds that favors regenerative wound healing over tissue fibrosis and scarring. It provides a significant framework for the potential use of an easy-to-produce parasite protein as a therapy to promote cutaneous wound healing.”
