The 22^nd annual meeting of the European Tissue Repair Society (ETRS) in Athens, Greece

Pathological healing is a leading cause of morbidity and mortality despite significant advance of wound care in the 20^th century. Severely injured organs cannot always be regenerated by the routine repair mechanisms of the body, thus necessitating the development of novel therapies. The 22^nd Annual Meeting of the European Tissue Repair Society (ETRS) was organized by Dimitris Kletsas and colleagues in Athens, Greece, from October 4 to 5, 2012 with almost 200 clinical and fundamental scientist attendees (Figure 1).

The 15 main sessions of the ETRS Annual Meeting [http://www.etrs.org] and the 60 posters on display covered the role of stem cells and cell therapies, growth factors (GF), angiogenesis, mechanical factors, biomaterials and nanotechnology, cell senescence, inflammation, and cell-extracellular matrix (ECM) interactions in tissue repair and regeneration (abstracts published in Wound Repair and Regeneration 2012, Volume 20(5)). Special sessions discussed infections, burns and chronic wounds, systems biology approaches to understand tissue repair, and the similarity between wound repair and cancer development. The ETRS meeting also hosted workshops given by the industry partners Integra and Bruker, and a guest session from the European Wound Management Association (EWMA). The proteomics workshop by Bruker was organized in collaboration with the ETRS Junior Committee, expressing the aim of ETRS to involve and support young scientists. Traditionally, ETRS meetings provide a platform for young investigators and more than 30 talks were selected from early stage researchers, of which nine competed in the Young Investigator’s Award session. This year’s winner was Eirini Apostolou (Biomedical Research Foundation Academy of Athens, Greece), who will be invited to present at the 2013 Annual Meeting of the ETRS partner organization, the Wound Healing Society (WHS), in Denver, Colorado. The next annual meeting of the ETRS will be organized from October 23–25 in Reims, in the beautiful Champagne region of France. Hands-on research on antioxidants is to be expected.

A main focus of the meeting was the use of MSCs to improve tissue repair and regeneration when the body’s repair mechanisms fail. MSCs contribute directly to tissue repair by exerting remodeling activity and by additionally exerting immunosuppressive, trophic, antiseptic, chemotactic, and differentiating effects on other cell populations in the wound environment. Furthermore, MSCs have been proposed as drug and gene-delivery vehicles and a number of methods have been presented to prepare MSCs for implantation purposes into different organs. In addition to the best characterized bone-marrow-derived MSCs, MSCs derived from adipose tissue or oral gingiva were introduced as attractive new cell sources to repair scarring burn skin wounds and chronic wounds, as well as to support the regeneration of diseased liver. For tissue regeneration of the soft palate of the cleft lip, MSCs derived from limb and head muscles were compared with respect to their differentiation potential. Moreover, bulge cells derived from hair follicles have been shown to provide a potential source of cells for wound repair. In addition to presenting the scientific and clinical potential of MSCs, practical aspects were discussed at the meeting, such as tissue and cell banking and drawbacks of the changing EU legislation concerning the use of stem cells.

The meeting sensitized all attendees to the fact that the chemical and mechanical conditions present in different injured tissues are important determinants of the cellular repair process and have to be considered for the development of treatment strategies for tissue regeneration. In cartilage, steep gradients of oxygen, glucose, and pH between the surface and the interior are generated due to the avascular nature of the tissue. Different dental scaffolds for tooth repair were shown to have different suitability for use with different oral-derived MSCs. In skin regeneration, it is important to suppress potential fibrotic characteristics of MSCs induced by expansion cell culture. Similarly, culture-induced senescence of MSCs was flagged as being detrimental for wound healing and tissue regeneration because of the pro-inflammatory state of senescent MSCs.

The mechanical conditions present in tissue under repair, such as strain and ECM stiffness, were highlighted as particularly important factors for the repair success. Extracellular proteins including Periostin and Cartilage oligomeric matrix protein (COMP) provide cell information on the physical state of the ECM. This mechanical information is perceived through integrin containing cell-ECM adhesions. The specific roles of different integrins were discussed for epithelial and fibroblast cell differentiation and different knock-out models were phenotyped. Cell-ECM adhesions and transmembrane integrins are intracellularly linked to the actin/myosin cytoskeleton. It was shown that cell shape, dictated by the ECM configuration, regulates internal stress and the polymerization degree of actin. In turn, the content of globular actin controls the translocation of the myocardin-related transcription factor MRTF from the cytosol to the nucleus and thus, stress-dependent gene expression. Another mechanotransduction pathway involves the activation of the JAK/STAT pathway, and a new link between the mechanical activation of TGFβ1 and ECM stiffness was revealed.

Modulation of mechanical stress is clinically exploited to improve chronic wound healing. With more than 20 different NPWT systems on the market, the search for their mechanisms of action has revealed mechanical stress as a critical component of NPWT therapy success. Negative pressure induces tissue macro- and micro-deformations and fluid shear forces that impact the activity of fibroblasts, blood vessels and lymphatics, in combination with the material properties of the NPWT foam.

Cancer development is similarly driven by the mechanical properties present in the stroma. The similarities in growth factor signaling, neo-vascularization and tissue remodeling between cancer and wound healing was addressed in the Charles Lapière memorial keynote lecture given by Dr. Sabine Werner (Eidgenössische Technische Hochschule Zürich, Switzerland). Dr. Werner focused on three recently studied proteins in cancer and wound healing: 1) perioxyredoxin 6 seems to protect skin from development of benign tumors by controlling lipid and protein oxidation but conversely promotes transition of benign to malignant tumors by protecting cancer cells from oxidative stress; 2) the transcription factor Nrf3 is downregulated during epidermal healing in keratinocytes and seems to be a negative regulator of normal healing; and 3) the transcription factor Nrf2 is highly expressed in suprabasal keratinocytes in the skin epidermis and regulates the antioxidant defense system. Constitutively active Nrf2 expressed under a keratinocyte-specific promoter protects from tumorigenesis but leads to ichtyosis and hyperkeratosis. The potential of pharmacological activators of Nrf2 in affecting tumorigenesis is currently under investigation. A number of other talks underlined that various ECM molecules which are important during wound healing influence cancer malignancy; in turn, cancer cells modulate the expression of ECM molecules in the stroma. For instance, paracrine factors released by breast cancers cells stimulate endothelial cells to express hyaluronic acid, its receptor CD44 and the adhesion molecules VCAM and ICAM. In turn, MT1-matrix metalloproteinase expression and endothelial cell migration are reduced. Collectively, it became evident at the meeting that knowledge and therapies generated in the field of cancer research are of tremendous use for chronic and excessive wound healing and vice versa.