The 22nd annual meeting of the European TissueRepair Society (ETRS) in Athens, GreeceHinz et al.

Hinz et al. Fibrogenesis & Tissue Repair 2013, 6:3http://www.fibrogenesis.com/content/6/1/3

Hinz et al. Fibrogenesis & Tissue Repair 2013, 6:3http://www.fibrogenesis.com/content/6/1/3

MEETING REPORT Open Access

The 22nd annual meeting of the European TissueRepair Society (ETRS) in Athens, GreeceBoris Hinz1*, Magda Ulrich2, Hilde Beele3 and Dimitris Kletsas4

Abstract

The 22nd Annual Meeting of the European Tissue Repair Society, Athens, Greece, October 4 to 5, 2012 informedabout pathophysiological mechanisms in tissue repair and on the development of clinical treatments of chronicwounds, fibrosis, and cancer, considering recent advances in molecular biology and biotechnology.

Keywords: Tissue repair, Wound healing, Fibrosis, Chronic wounds, Stem cells

IntroductionPathological healing is a leading cause of morbidity andmortality despite significant advance of wound care inthe 20th century. Severely injured organs cannot alwaysbe regenerated by the routine repair mechanisms of thebody, thus necessitating the development of novel ther-apies. The 22nd Annual Meeting of the European TissueRepair Society (ETRS) was organized by Dimitris Kletsasand colleagues in Athens, Greece, from October 4 to 5,2012 with almost 200 clinical and fundamental scientistattendees (Figure 1).The 15 main sessions of the ETRS Annual Meeting

[http://www.etrs.org] and the 60 posters on display coveredthe role of stem cells and cell therapies, growth factors(GF), angiogenesis, mechanical factors, biomaterials andnanotechnology, cell senescence, inflammation, and cell-extracellular matrix (ECM) interactions in tissue repair andregeneration (abstracts published in Wound Repair andRegeneration 2012, Volume 20(5)). Special sessions dis-cussed infections, burns and chronic wounds, systems biol-ogy approaches to understand tissue repair, and thesimilarity between wound repair and cancer development.The ETRS meeting also hosted workshops given by the in-dustry partners Integra and Bruker, and a guest sessionfrom the European Wound Management Association(EWMA). The proteomics workshop by Bruker was or-ganized in collaboration with the ETRS Junior Committee,expressing the aim of ETRS to involve and support young

* Correspondence: boris.hinz@utoronto.ca1Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group,Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ONM5S3E2, CanadaFull list of author information is available at the end of the article

© 2013 Hinz et al.; licensee BioMed Central LtCommons Attribution License (http://creativecreproduction in any medium, provided the or

scientists. Traditionally, ETRS meetings provide a platformfor young investigators and more than 30 talks wereselected from early stage researchers, of which ninecompeted in the Young Investigator’s Award session. Thisyear’s winner was Eirini Apostolou (Biomedical ResearchFoundation Academy of Athens, Greece), who will beinvited to present at the 2013 Annual Meeting of the ETRSpartner organization, the Wound Healing Society (WHS),in Denver, Colorado. The next annual meeting of the ETRSwill be organized from October 23–25 in Reims, in thebeautiful Champagne region of France. Hands-on researchon antioxidants is to be expected.

The clinical impacts of poor and excessive healingThe Ying of wound healing - chronic woundsInsufficient healing causes a high level of mortality andmorbidity and is an important cost factor for the globalhealth care system. Chronic wounds are present in 2% ofthe patients in Western countries and 1% worldwide.Chronic wounds particular affect diabetics, physicallydisabled, elderly and patients with vascular diseases, aswas shown in a cross-sectional study performed in India.Finding effective treatments to restore normal healing inchronic wounds and measuring the outcomes are majorchallenges for clinical therapies, which was discussed inseveral talks. Risk factors include smoking, whereassmoking cessation and nicotine replacement therapy wasshown to improve healing. Other treatments include ne-gative pressure wound therapy (NPWT), and platelet-rich fibrin for general regeneration support.

d. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly cited.

http://www.etrs.orghttp://creativecommons.org/licenses/by/2.0

Figure 1 Official poster announcement of the 22nd AnnualMeeting of the European Tissue Repair Society, Athens, Greece,October 4 to 5, 2012.

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One major complication in chronic wounds is bacterialinfection. Mouse models demonstrate a systemic negativeeffect of local sepsis on the inflammatory response. Differ-ent concepts were presented to target/prevent bacterial in-fection and biofilm formation, including treatment withlocal polyhexamethylene biguanidine antiseptics. It waspostulated that in some cases, adequately used local anti-septics could prevent the need for systemic antibiotics.Novel concepts involve the use of dextrin-colistin poly-mers to interfere with biofilm growth and stability and todeliver GFs to the wound bed. Other innovative systemsthat may improve chronic wound healing include a non-viral piggyback transposon system for gene delivery andnanostructured polymer containers constructed of mag-netic nanoparticles to deliver GFs. Such GFs may includeEpidermal GF (EGF) to support re-epithelialization ortumor necrosis factor α to control ECM reorganization bymatrix metalloproteinases.Chronic wound healing is often associated with ische-

mia and with low levels of tissue O2 (hypoxia); hypoxiais accepted to be one of the main risk factors for chronicwounds. One session focused on the molecular mecha-nisms of angiogenesis as targets to support tissue

oxygenation. Several biomolecules were addressed, in-cluding anti-angiogenic molecules such as advancedglycation end products and pro-angiogenic moleculessuch as vascular endothelial GF (VEGF), nucleolin, talinand epoxyeicosatrienoic acids. The role of Interleukin-10 was discussed in a talk given by Swati Balaji (CincinnatiChildren’s Hospital Medical Center, Cincinnati, OH), theYoung Investigator Award winner of the Wound HealingSociety’s 2012 Annual Meeting.

The Yang of wound healing - fibrosis and contracturesExcessive healing involves the excessive and persistentaccumulation of ECM, inflammatory cells and repara-tive cells, which are common in organ fibrosis and skinhypertrophic scarring, such as after large area burns.According to the American Burn Association, approxi-mately 45% of patients with burn wounds died in theperiod 2001 to 2010 when more than 50% of the skinsurface was destroyed. Hypertrophic scars arise fromimperfect dermis regeneration and can immobilizedigits and limbs; furthermore, the poor esthetics of thescar enormously impact on the patient’s quality of life.A workshop organized by Integra presented ECM res-toration strategies to support the formation of a neo-dermis in burns and in post-traumatic and post-surgicalwounds.A number of talks discussed the molecular mecha-

nisms of fibrosis development in other organs andconditions. Deciphering common traits in the patho-physiological processes will be beneficial to developnovel anti-fibrosis strategies. Such approaches includesystems biology (for example, gene array meta-analysisof human keloid scars and control tissue, data analysisfrom a longitudinal human platform to model pro-cesses and pathways in variety of pathologies includingwound healing). A workshop organized by Brukerinformed researchers of the use, principles and instru-mentation of proteomic analysis for wound healingresearch. To identify processes involved in airway scar-ring, ex vivo organ cultures of early non-scarring andlate developmental stage scarring fetal rat airways werepresented as another model for detecting patterns ofpro-fibrotic gene clusters. In-depth analysis of selectedpathways and molecules was presented for the pro-fibrotic/wound healing supporting roles of TAK1, adownstream effector of non-Smad transforming GF β1(TGFβ1) signaling, the β2 adrenoceptor, Trefoil familyfactor 2 (TFF2) and CCN2 (Connective tissue growthfactor, CTGF). The pro-fibrotic cytokine TGFβ wasshown to play a major role in normal adult lung repair,whereas Bone morphogenetic protein (BMP) is preva-lent during development. The data suggested that dur-ing lung injury, BMP is expressed by cells with stem

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cell characteristics whereas TGFβ hallmarks differen-tiated cells.

Inflammation plays a role in chronic wound healing andfibrosisInflammatory cells can be both beneficial and detri-mental to the outcome of tissue and organ repair. Theinflammatory response and the hepatic regenerationpotential were compared in animal models of open andlaparoscopic left partial hepatectomy. The open surgi-cal procedure resulted in a higher systemic inflamma-tory response and improved liver regeneration. Viraloverexpression of Activin A in mouse lungs leads tochronic inflammation and generates a phenotype thatresembles human acute respiratory stress syndrome(ARDS). In another study, histatins were presented tosupporting re-epithelialization and wound healing, pos-sibly by modulating the inflammatory response. Inchronic wounds, macrophage polarization was presen-ted as a critical event in wound healing. Whereas thepro-inflammatory macrophage M1 type prevails inchronic wounds, a switch to the M2 macrophage ap-pears to improve healing. This switch can be inducedby delivered mesenchymal progenitor cells (MSCs).

The use of multipotent mesenchymal progenitorcells (MSCs) for improved tissue repairA main focus of the meeting was the use of MSCs toimprove tissue repair and regeneration when the body’srepair mechanisms fail. MSCs contribute directly totissue repair by exerting remodeling activity and by add-itionally exerting immunosuppressive, trophic, antisep-tic, chemotactic, and differentiating effects on other cellpopulations in the wound environment. Furthermore,MSCs have been proposed as drug and gene-deliveryvehicles and a number of methods have been presentedto prepare MSCs for implantation purposes into differ-ent organs. In addition to the best characterized bone-marrow-derived MSCs, MSCs derived from adiposetissue or oral gingiva were introduced as attractive newcell sources to repair scarring burn skin wounds andchronic wounds, as well as to support the regenerationof diseased liver. For tissue regeneration of the soft pal-ate of the cleft lip, MSCs derived from limb and headmuscles were compared with respect to their differenti-ation potential. Moreover, bulge cells derived from hairfollicles have been shown to provide a potential sourceof cells for wound repair. In addition to presenting thescientific and clinical potential of MSCs, practical as-pects were discussed at the meeting, such as tissue andcell banking and drawbacks of the changing EU legisla-tion concerning the use of stem cells.

The microenvironment affects the regenerativepotential of reparative cellsThe meeting sensitized all attendees to the fact that thechemical and mechanical conditions present in differentinjured tissues are important determinants of the cellu-lar repair process and have to be considered for the devel-opment of treatment strategies for tissue regeneration. Incartilage, steep gradients of oxygen, glucose, and pH be-tween the surface and the interior are generated due to theavascular nature of the tissue. Different dental scaffolds fortooth repair were shown to have different suitability for usewith different oral-derived MSCs. In skin regeneration, it isimportant to suppress potential fibrotic characteristics ofMSCs induced by expansion cell culture. Similarly, culture-induced senescence of MSCs was flagged as being detri-mental for wound healing and tissue regeneration becauseof the pro-inflammatory state of senescent MSCs.The mechanical conditions present in tissue under re-

pair, such as strain and ECM stiffness, were highlightedas particularly important factors for the repair success.Extracellular proteins including Periostin and Cartilageoligomeric matrix protein (COMP) provide cell informa-tion on the physical state of the ECM. This mechanicalinformation is perceived through integrin containingcell-ECM adhesions. The specific roles of different inte-grins were discussed for epithelial and fibroblast celldifferentiation and different knock-out models werephenotyped. Cell-ECM adhesions and transmembraneintegrins are intracellularly linked to the actin/myosincytoskeleton. It was shown that cell shape, dictated bythe ECM configuration, regulates internal stress and thepolymerization degree of actin. In turn, the contentof globular actin controls the translocation of themyocardin-related transcription factor MRTF from thecytosol to the nucleus and thus, stress-dependent geneexpression. Another mechanotransduction pathway in-volves the activation of the JAK/STAT pathway, and anew link between the mechanical activation of TGFβ1and ECM stiffness was revealed.Modulation of mechanical stress is clinically exploited to

improve chronic wound healing. With more than 20 differ-ent NPWT systems on the market, the search for theirmechanisms of action has revealed mechanical stress as acritical component of NPWT therapy success. Negativepressure induces tissue macro- and micro-deformationsand fluid shear forces that impact the activity of fibroblasts,blood vessels and lymphatics, in combination with the ma-terial properties of the NPWT foam.

The similarities between tissue repair and cancerCancer development is similarly driven by the mechanicalproperties present in the stroma. The similarities ingrowth factor signaling, neo-vascularization and tissueremodeling between cancer and wound healing was

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addressed in the Charles Lapière memorial keynote lecturegiven by Dr. Sabine Werner (Eidgenössische TechnischeHochschule Zürich, Switzerland). Dr. Werner focused onthree recently studied proteins in cancer and woundhealing: 1) perioxyredoxin 6 seems to protect skin fromdevelopment of benign tumors by controlling lipid andprotein oxidation but conversely promotes transition ofbenign to malignant tumors by protecting cancer cells fromoxidative stress; 2) the transcription factor Nrf3 is down-regulated during epidermal healing in keratinocytes andseems to be a negative regulator of normal healing; and 3)the transcription factor Nrf2 is highly expressed insuprabasal keratinocytes in the skin epidermis and regulatesthe antioxidant defense system. Constitutively active Nrf2expressed under a keratinocyte-specific promoter protectsfrom tumorigenesis but leads to ichtyosis and hyperkera-tosis. The potential of pharmacological activators of Nrf2 inaffecting tumorigenesis is currently under investigation.A number of other talks underlined that various ECMmolecules which are important during wound healing influ-ence cancer malignancy; in turn, cancer cells modulate theexpression of ECM molecules in the stroma. For instance,paracrine factors released by breast cancers cells stimulateendothelial cells to express hyaluronic acid, its receptorCD44 and the adhesion molecules VCAM and ICAM. Inturn, MT1-matrix metalloproteinase expression and endo-thelial cell migration are reduced. Collectively, it becameevident at the meeting that knowledge and therapiesgenerated in the field of cancer research are of tremendoususe for chronic and excessive wound healing and vice versa.

AbbreviationsARDS: Acute respiratory stress syndrome; BMP: Bone morphogenetic protein;COMP: Cartilage oligomeric matrix protein; ECM: Extracellular matrix;EGF: Epidermal growth factor; ETRS: European Tissue Repair Society;EWMA: European Wound Management Association; GF: Growth factor;MRTF: Myocardin-related transcription factor; MSC: Mesenchymal stromal cell;NPWT: Negative pressure wound therapy; TGF: Transforming growth factor;TFF2: Trefoil family factor 2; VEGF: Vascular endothelial growth factor;WHS: Wound Healing Society.

Competing interestsThe authors state that they have no competing interests.

Authors’ contributionsBH contributed to the writing of 50% and coordinated the manuscript. MU,HB and DK contributed to the other 50%. All authors have read andapproved the final manuscript.

AcknowledgementsThe research of BH is supported by the Canadian Institutes of HealthResearch (grant #210820), the Collaborative Health Research Programme(CIHR/NSERC) grants #1004005 and #413783, the Canada Foundation forInnovation and Ontario Research Fund (grant #26653), and the Heart andStroke Foundation Ontario (grant #NA7086). MU is supported by the DutchBurns Foundation. HB receives funding from the Ghent University and DK issupported by the EU (HEALTH-F2-2008-201626).

Author details1Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group,Faculty of Dentistry, University of Toronto, 150 College Street, Toronto, ONM5S3E2, Canada. 2Association of Dutch Burn Centres, Beverwijk, The

Netherlands and Department of Plastic Reconstructive and Hand Surgery, VUUniversity Medical Center, Amsterdam, The Netherlands. 3Department ofDermatology and Tissue Bank, Ghent University Hospital, Ghent, Belgium.4Laboratory of Cell Proliferation and Ageing, Institute of Biology, NationalCentre of Scientific Research “Demokritos”, 15310, Athens, Greece.

Received: 27 November 2012 Accepted: 11 January 2013Published: 1 February 2013

doi:10.1186/1755-1536-6-3Cite this article as: Hinz et al.: The 22nd annual meeting of the EuropeanTissue Repair Society (ETRS) in Athens, Greece. Fibrogenesis & TissueRepair 2013 6:3.

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AbstractIntroductionThe clinical impacts of poor and excessive healingThe Ying of wound healing - chronic woundsThe Yang of wound healing - fibrosis and contracturesInflammation plays a role in chronic wound healing and fibrosis

The use of multipotent mesenchymal progenitor cells (MSCs) for improved tissue repairThe microenvironment affects the regenerative potential of reparative cellsThe similarities between tissue repair and cancerAbbreviationsCompeting interestsAuthors’ contributionsAcknowledgementsAuthor details