Researchers at Rutgers University have discovered that a protein produced by an intestinal parasite, Heligmosomoides polygyruscan be used to improve wound healing in mice. The study showed that applying the protein TGF-β mimetic (TGM) to skin wounds under a Tegaderm dressing accelerated wound closure, improved skin regeneration, and inhibited the formation of scar tissue. In their published work in Life Sciences AllianceThe researchers, led by William C. Gause, PhD, director of the Center for Immunity and Inflammation at Rutgers University, commented that the results of their study in mice “… demonstrate that topical application of TGM both promotes wound healing and produces an overall positive long-term outcome in standard wound care.”
Their published report is titled “Helminth protein improves wound healing by inhibiting fibrosis and promoting tissue regeneration.”
Skin is an important barrier and defense mechanism in mammals, and after injury, the body must quickly activate a wound healing response, the authors wrote. “Wound healing 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 healing process involves three major overlapping phases: inflammation, proliferation and maturation, they continued. During the inflammatory phase, several cell types are recruited to the wound area immediately after injury. During proliferation, endothelial cells, macrophages and fibroblasts are activated, covering the wound. The final maturation phase involves the production and deposition of the extracellular matrix. However, rapid wound closure may favor the development of scar tissue instead of properly regenerated skin. “Fibrosis is often associated with the healing of skin wounds,” they wrote. “It results in tissue scarring rather than regeneration and is considered a significant public health burden, costing billions of dollars each year.”
The balance between scar formation and successful tissue regeneration is strongly influenced by the immune cells recruited to the wound, the team continued. “After wound closure, the maturation phase of wound healing involves the recruitment and activation of different immune cell populations that can influence whether the healing process favors a profibrotic pathway associated with scar formation or a more favorable proregenerative pathway.” Many researchers are interested in finding ways to increase the activity of immune cell types that promote regeneration while inhibiting the activity of immune cells that promote tissue scar formation. “Developing a treatment that both rapidly suppresses harmful inflammatory responses and induces the expression of tissue repair factors that favor tissue regeneration over scar formation could promote more effective wound healing and lead to better clinical outcomes,” the researchers continued.
Recent studies have shown that excretory/secretionary molecules (ES) produced by parasitic worms may modulate the host immune system in a way that promotes tissue regeneration. “A recently discovered ES protein, TGF-β mimetic (TGM), binds the TGF-β receptor but likely has other activities as well.” The TGF-β receptor is found on the surface of many cell types in mice and humans, including immune cells.
TGM is an ES of Heligmosomoides polygyrusa parasitic roundworm that lives in the intestines of mice and other rodents. Interestingly, the team said, previous studies had reported that “TGM exerts anti-inflammatory effects in vivo in models of colitis, transplant rejection, and respiratory allergy.”
The recent availability of large quantities of recombinant, highly purified TGM made it possible to conduct further in vivo analyses. For their research, Gause, first author Dr. Katherine E. Lothstein, and colleagues conducted a series of in vitro tests and in vivo studies in mice to assess whether administration of H. polygyrus ES products (HES), and particularly TGM, may promote tissue repair and modulate the course of skin wound healing. “We administered the recently identified recombinant TGM molecule, originally isolated from helminth ES products, directly under a protective Tegaderm dressing,” they wrote.
Their experiments found that daily topical application of TGM combined with the use of a Tegaderm dressing accelerated the closure of skin wounds in mice. In addition, TGM treatment reduced scar tissue formation and improved skin regeneration. Unlike untreated animals, mice treated with TGM were able to form new hair follicles in the injured skin area. “…complete sebaceous glands and hair shafts were observed in the TGM-treated wounds, indicating normal skin development associated with tissue regeneration,” they wrote.
TGM treatment appeared to stimulate the recruitment of immune cells called macrophages into wounds and reprogram them to promote tissue regeneration. The data, the researchers said, “… demonstrate that TGM alters the macrophage landscape in tissues undergoing wound healing responses. Taken together, these analyses suggest that macrophages induced following TGM treatment generally exhibit reduced expression of CD206 but upregulation of many markers associated with M2 macrophages and the wound healing process.”
The team pointed out that TGM is easy to manufacture as a recombinant product and can be standardised for treatment in combination with a bioocclusive dressing such as Tegaderm. They acknowledged that further research will be needed to investigate whether the protein can be used to improve wound healing in human patients.
In their discussion, the scientists concluded: “Taken together, these studies provide an important framework for the potential use of a highly purified helminth ES product as a therapy to promote skin wound healing.” Gause added: “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 an important framework for the potential use of an easily manufactured parasite protein as a therapy to promote skin wound healing.”
