The interdisciplinary research project “Skintegrity” has succeeded in developing a new method for measuring the biomechanical properties of healing tissue in vivo. In addition to the role of Activin A in wound healing processes, new insights have been gained into the importance of this signal molecule in the development of skin tumors.
The goal of the research team of scientists from ETH and the University of Zurich is to improve diagnostic and therapeutic options in the field of skin diseases and skin defects based on the identification of new factors that promote healing. Current study projects focus on the signal molecule Activin. It is a representative of the TGF-β family of growth and differentiation factors. Previous studies have shown that activin A expression is induced by skin injury, both in mice and humans. “This is functionally relevant, because inhibition of activin slows wound healing, but fortunately it also inhibits scar formation. Conversely, we were able to show that overexpression of Activin A in the skin accelerates wound healing,” explains Prof. Dr. Sabine Werner, Professor of Cell Biology, Institute of Molecular Health Sciences, ETH Zurich [1]. In a recent study published in the journal Nature Communications, the research team investigated mechanisms of normal and hypertrophic scarring and identified targets for therapeutic intervention [2]. This represents a further step towards unraveling the complex mechanisms that control the process of wound healing and scar formation.
Fig. 1: Subprojects of “Skintegrity
modified according to [3]
Scar-free wound healing as a long-term goal
An increase in activin in the wound correlates with increased development of connective tissue cells and a change in the composition of the extracellular matrix. In this scaffold, which is produced by the cells and surrounds them, more collagen accumulates at increased Activin concentrations and the collagen fibers are also more interconnected among themselves. This causes the wound to heal more quickly, but the injured tissue stiffens and hardens. Within the framework of “Skintegrity”, the interdisciplinary research team led by Prof. Dr. Edoardo Mazza, ETH Zurich, has now succeeded in developing a method with which the biomechanical properties of a healing tissue can be measured in vivo. In the future, this could allow the healing process of a wound to be diagnosed at an early stage and perhaps even influenced. If an impending chronic course of a wound becomes apparent, an intervention could be conceivable which leads to an enrichment of Activin or Activin-influenced matrix proteins and thus accelerates the healing process. In the case of facial injuries, on the other hand, a method that slows down the healing process and reduces scarring would be more appropriate. “A clinical application is the ultimate goal,” Prof. Werner said. Currently, this is still a vision of the future, but the cross-disciplinary collaboration within the research project “Skintegritiy” allows a synergistic use of scientific, technical and clinical know-how at the highest level and new empirical data are continuously generated [3].
| Flagship project “Skintegrity To gain a detailed understanding of the molecular, cellular and biomechanical mechanisms underlying normal and impaired wound healing as well as various skin diseases, Hochschulmedizin Zürich launched the project “Skintegrity” in 2016. It combines the expertise of 30 research groups at ETH, the University of Zurich and associated university clinics. In close collaboration, physicians, biologists, materials scientists and engineers are developing new methods and approaches with the aim of better diagnosing and treating important skin diseases and wound healing disorders. www.hochschulmedizin.uzh.ch/de/projekte/skintegrity.htm |
Molecular paralells between wound healing and skin tumors.
Activin A plays an important role in wound healing as well as cancer. In the mouse model it could be shown that increased activin concentrations in the skin promote tumorigenesis and thus it is a functionally relevant factor for tumorigenesis [4]. “In biopsies of basal cell and squamous cell carcinomas, there is a 5- to 50-fold overexpression of this growth factor,” Prof. Werner said. This occurs in an early phase of skin carcinogenesis and has also been observed in patients suffering from actinic keratosis. “Activin is clearly a tumor-promoting molecule in the skin,” summarizes the researcher. In a recent publication, the mechanism underlying the tumor-promoting effect of Activin was elucidated [5]. Activin A expressed in cancer cells was shown to reprogram fibroblasts into cancer-associated fibroblasts (CAFs). Activin receptor antagonists are currently being investigated in clinical trials for the treatment of myeloma-induced bone loss, chemotherapy-induced anemia, and cancer-induced muscle loss [1]. A possible application of these substances for the treatment of skin cancer is an interesting option to be tested in further work.
Literature:
- Werner S: Skintegrity and wound healing research. Prof. Dr. Sabine Werner, Zürcher Dermatologische Fortbildungstage (ZDFT) 14./15.05.2020.
- Wietecha MS, et al: Nature Communications 2020; 11: May 25. doi: 10.1038/s41467-020-16409-z
- Skintegrity, www.hochschulmedizin.uzh.ch/de/projekte/skintegrity/projekt-details.html
- Antsiferova M, et al: Nat Commun 201; 2: 576. doi: 10.1038/ncomms1585.
- Cangkrama M, et al: EMBO Mol Med 2020; 12(4):e11466. doi: 10.15252/emmm.201911466. epub 2020 Mar 9.
DERMATOLOGIE PRAXIS 2020; 30(4): 40-42 (published 8/24/20, ahead of print).
