Welcome to the Werner lab!
Our laboratory studies the molecular and cellular mechanisms of tissue repair, with particular emphasis on the roles of growth factors and their downstream targets in this process. In particular, we are interested in the parallels between wound healing and cancer at the cellular and molecular level.
Injury to adult tissues initiates a series of events, which finally lead to at least partial reconstruction of the injured body site. With the exception of the liver, which can completely regenerate in most cases, repair of other organs is imperfect and results in scar formation with functional impairments (Gurtner et al., 2008). There are many conditions in humans, which are associated with impaired tissue repair, including old age, steroid treatment and several diseases such as diabetes and cancer. Therefore, there is a strong need to improve the healing process. This requires a detailed understanding of the underlying cellular and molecular mechanisms. By trying to elucidate these mechanisms, our research shall help to develop new strategies for the improvement of tissue repair, in particular of cutaneous wound repair. To achieve these goals, we use state-of-the art approaches, including functional genomics and proteomics, organotypic cell culture systems, and genetically modified mice.
An exciting aspect of our research is the analysis of the parallels between tissue repair and cancer at the molecular and cellular level (Schäfer and Werner, 2008). We identify and functionally characterize genes and signaling pathways, which orchestrate both processes, with a focus on the role of growth factors and transcriptional regulators in tissue repair and cancer. We use the mouse as a model organism to address these questions. Collaboration with clinical partners will help to determine the importance of our findings for the human situation and to transfer our research results into clinical practice.
Cited References from our laboratory can be found under "Publications".
Fibroblast growth factors and activin in tissue homeostasis, repair and disease (currently funded by ETH Zürich, Swiss National Science Foundation, Swiss Cancer League, Studienstiftung des Deutschen Volkes; previously funded by Roche Foundation, Deutsche Forschungsgemeinschaft, Boehringer Ingelheim Fonds, Janggen-Pöhn Foundation, Leopoldina, Schering Foundation, China Scholarship Council, Swiss Government).
- Dr. Michael Cangkrama () (from Indonesia/Australia)
- Dr. Abbie Fearon () (from England)
- Luca Ferrarese () (from Italy)
- Fumimasa Kubo () (from Japan)
- Theresa Rauschendorfer () (from Germany)
- Catharina Sänger () (from Germany)
- Dr. Kristin Seltmann () (from Germany)
- Coenraad Slabber () (from South Africa)
- Dr. Deborah Stefanova ( (from Bulgaria)
- Dr. Corinne Urwyler () (from Switzerland)
- Dr. Mateusz Wietecha () (from USA/Poland)
- Till Wüstemann () (from Germany)
- Dr. Shen Yan () (from China)
- Karin Angermeyer (from Germany)
- Dr. Maria Antsiferova () (from Russia)
- Dr. Marc Bachofner () (from Switzerland)
- Dr. Casimir Bamberger () (from Germany)
- PD Dr. Hans-Dietmar Beer () (from Germany)
- Dr. Tobias Beyer () (from Switzerland)
- Katharina Blatter () (from Switzerland)
- Dr. Kerstin Bleuel () (from Germany)
- Dr. Katharina Birkner () (from Germany)
- Dr. Friederike Böhm () (from Germany)
- Dr. Susanne Braun () (from Germany)
- Dr. Maria Brauchle () (from Germany)
- Dr. Philippe Bugnon () (from Switzerland)
- Dr. Johanna Dammeier (johanna.dammeier@ uni-tuebingen.de) (from Germany)
- Irene Dick (from Germany)
- Silke Durka () (from Germany)
- Dr. Felix Engelhardt () (from Germany)
- Prof. Dr. Stefan Frank () (from Germany)
- Dr. Richard Grose () (from England)
- Dr. Marcus Gassmann () (from Germany)
- Dr. Eric Haertel () (from Germany)
- Dr. Tobias Heatta-Speicher () (from Germany)
- Dr. Moritz Hertel () (from Germany)
- Dr. Griseldis Hübner () (from Germany)
- Katharina Huggel () (from Switzerland)
- Dr. Susanne Kaesler () (from Germany)
- Dr. Heidi Kögel () (from Germany)
- Dr. Katalin Korodi () (from Hungary)
- Dr. Monika Krampert () (from Germany)
- Dr. Luigi Maddaluno () (from Italy)
- Dr. Marianne Madlener () (from Germany)
- Dr. Michael Meyer () (from Switzerland/South Africa)
- Michelle Meyer () (from Switzerland)
- Dr. Anna-Katharina Müller () (from Switzerland)
- Dr. Mischa Müller () (from Switzerland)
- Dr. Christine Munding (from Germany)
- Prof. Dr. Barbara Munz () (from Germany)
- Prof. Dr. Khondokar Nasirujjaman () (from Bangladesh)
- Dr. Susagna Padrissa-Altes () (from Spain)
- Dr. Sandra Pankow () (from Germany)
- Dr. Aleksandra Piwko-Czuchra () (from Poland)
- Dr. Tamara Ramadan (from Croatia)
- Helga Riesemann (from Germany)
- Dr. Diana Rotzer () (from Germany)
- Andreas Stanzel () (from Germany)
- Dr. Heike Steiling () (from Germany)
- Dr. Jitka Sulcova () (from Czech Republic)
- Dr. Silke Sulyok (Werner) () (from Germany)
- Dr. Irmgard Thorey () (from Germany)
- Dr. Laurence Vindevoghel () (from France)
- Dr. Elina Virolainen (from Finland)
- Dr. Miriam Wankell () (from Germany)
- Frédérique Wanninger (from Germany)
- Prof. Dr. Jingxuan Yang () (from China)
Fibroblast growth factors
Fibroblast growth factors (FGFs) comprise a family of 22 proteins, which play important roles in development, tissue homeostasis, repair and disease. We are particularly interested in FGF7, which is also called keratinocyte growth factor (KGF) (Werner, 1998). FGF7 is a secreted protein, which is produced by various types of mesenchymal cells and by T cells, but not by epithelial cells. However, epithelial cells express FGFR2b, the only known high-affinity receptor for FGF7. FGF7 is weakly expressed in normal skin, but strikingly upregulated in dermal fibroblasts after skin injury (Werner et al., 1992). By contrast, FGFR2b is expressed on keratinocytes of the epidermis and the hair follicles, suggesting that FGF7 stimulates wound reepithelialization in a paracrine manner. This hypothesis was supported by the strong delay in wound healing in transgenic mice, which express a dominant-negative FGFR2b mutant in the basal keratinocytes of the epidermis (Werner et al., 1994), and in mice lacking FGFR1 and FGFR2 in keratinocytes (Meyer et al., 2012). Mechanistically, this was caused by impaired migration of FGFR1/FGFR2-deficient keratinocytes due to reduced expression of focal adhesion proteins (Meyer/Müller et al., 2012; Fuhr/Meyer et al., 2015).
FGFs are also important regulators of skin morphogenesis and homeostasis. Thus, mice lacking FGFR1b and FGFR2b in keratinocytes develop cutaneous inflammation, keratinocyte hyperproliferation and acanthosis with strong similarities to Atopic Dermatitis in humans (Yang/Meyer et al., 2010; Sulcova et al., 2015; Seltmann/Meyer et al., 2018). We identified loss of FGF-induced expression of tight junction components with subsequent deficits in epidermal barrier function as the mechanism underlying the progressive inflammatory skin disease. These results identified essential roles for FGFs in the regulation of the epidermal barrier and in the prevention of cutaneous inflammation and highlight the importance of stromal-epithelial interactions in skin homeostasis and disease (Yang/Meyer et al., 2010; Meyer et al., 2011; Sulcova et al., 2015a,b, Meyer et al., 2020). Since Atopic Dermatitis symptoms frequently aggravate at low environmental humidity, e.g. during the dry winter season, we exposed the FGFR-deficient mice that develop Atopic Dermatitis-like symptoms to a higher humidity. Remarkably, even a short-term maintenance of the mice at 70% humidity rescued the inflammatory phenotype. Using a combination of quantitative proteomics and functional cell biology we identified the mechanisms underlying the response of the skin to low environmental humidity and discovered a novel osmo-regulated protein in keratinocytes that is upregulated in response to hyperosmolarity/skin dryness to maintain the epidermal integrity under stress conditions, such as in patients with Atopic Dermatitis (Seltmann/Meyer et al., 2018).
In our recent work, we discovered an unexpected antagonism between FGF and interferon signaling. Thus, FGF receptor activation in epithelial cells strongly suppressed the interferon response, resulting in a higher susceptibility to infection with different viruses. Vice versa, FGF receptor inhibition had potent antiviral activities in vitro, ex vivo and in vivo. These results suggest the use of FGF receptor antagonists for the treatment of viral infections (Maddaluna/Urwyler/ Rauschendorfer et al., 2020).
FGF7 also exerts potent cytoprotective activities. Thus, it can protect intestinal epithelial cells from cell death induced by radiation and chemotherapy, and it has been approved for the treatment of mucositis in cancer patients. We confirmed the cytoprotective effect of FGF7 for the skin, and we demonstrated that FGF7 protects keratinocytes from UV- or toxin-induced cell death by stimulating the expression of various genes involved in the control of the cellular redox homeostasis (Braun et al., 2006). Of particular importance is the Nrf2 transcription factor, which we characterize with regard to its functions in tissue repair, inflammatory disease and cancer (see project 2).
In analogy to our findings on FGFs in wound healing, we also found a crucial role of FGFR signaling in liver regeneration (Steiling et al., 2003) and in the pathogenesis of liver fibrosis and cirrhosis (Steiling et al., 2004). Specifically, loss of FGFR1 and FGFR2 in hepatocytes caused a severe deficiency in compound detoxification in the regenerating liver through regulation of circadian transcription factors that control various detoxifying enzymes (Böhm et al., 2010). Most importantly, combined loss of FGFR1, FGFR2 and FGFR4 in hepatocytes resulted in liver failure after partial hepatectomy, demonstrating that FGFR signaling is essential for liver regeneration (Padrissa-Altes et al., 2014). Additional projects on liver regeneration revealed that both 1-integrin and the ubiquitin ligase Nedd4-1 regulate growth factor signaling in the regenerating liver and thereby strongly contribute to the regeneration process (Speicher et al., 2014; Bachofner/Speicher et al., 2017).
Activins are members the TGF- superfamily of growth and differentiation factors, which influence proliferation and differentiation of many different cell types. In recent years, we demonstrated important roles of activin in skin homeostasis and repair. Thus, we found a strikingly increased expression of activin after skin wounding (Hubner et al., 1996). This is functionally important, since overexpression of activin in basal keratinocytes of the epidermis of transgenic mice strongly accelerated wound reepithelialization and granulation tissue formation. The healing-promiting effect is mediated by different types of immune cells and in particular by fibroblasts (Munz et al., 1999, Antsiferova et al., 2013; Haertel et al., 2018; Wietecha et al., 2020). However, we also found enhanced scarring in these mice, which resulted from activin-induced expression of pro-fibrotic genes (Wietecha et al., 2020). Vice versa, inhibition of activin action during wound healing by overexpression of its secreted antagonist follistatin strongly delayed the wound healing process (Wankell et al., 2001).
Due to the parallels between wound healing and cancer, we speculated about a role of activin in the pathogenesis of skin cancer. Using different types of genetically modified mice we showed that enhanced levels of activin in the skin promote skin tumor formation and their malignant progression through induction of a pro-tumorigenic microenvironment. This included accumulation of tumor-promoting Langerhans cells and regulatory T cells in the epidermis and of mast cells in the dermis (Antsiferova et al., 2011 and 2013). Furthermore, activin inhibited proliferation of tumor-suppressive epidermal T cells, resulting in their progressive loss during tumor promotion. It also enhanced the number of macrophages in pre-tumorigenic skin lesions and promoted their differentiation into a phenotype resembling tumor- associated macrophages. This is functionally relevant, since depletion of macrophages reduced activin-induced skin carcinogenesis (Antsiferova et al., 2017). Finally, activin A overexpression strongly promoted the reprogramming of normal skin fibroblasts into cancer-associated fibroblasts through a novel Activin A-mDia2-p53 signaling axis (Cangkrama et al., 2020). The human relevance of these results is reflected by the strongly increased expression of activin in cutaneous basal and squamous cell carcinomas and already in some skin cancer precursor lesions and by the negative correlation between Activin A/mDia2 expression with survival in different types of human cancers (Antsiferova et al., 2011; Cangkrama et al., 2020). These findings highlight the parallels between wound healing and cancer and suggest inhibition of activin action as a promising strategy for the treatment of cancers overexpressing this factor.
In addition to the skin, we provided evidence for an important role of activin in other types of inflammatory and repair processes (reviewed by Werner and Alzheimer, 2006). Finally, in collaboration with the laboratory of Prof. Christian Alzheimer at the University of Erlangen, Germany, we demonstrated an important role of activin in neuroprotection, synaptic plasticity, anxiety and depression (Tretter et al., 1996, 2000; Müller et al., 2006, Tseng et al., 2008, Link et al., 2016).
Role of the cytoprotective Nrf2 transcription factor and its target genes in tissue repair, inflammatory disease and cancer (currently funded by ETH Zürich, Swiss National Science Foundation, Innosuisse, Wilhelm Sander-Stiftung, Novartis Foundation, Topadur Pharma AG; previously funded by Boehringer Ingelheim Fonds, Deutsche Forschungsgemeinschaft, AETAS Foundation, EMBO, Promedica Foundation, Studienstiftung des Deutschen Volkes, CE.R.I.E.S. Award, Government of Canada, Helmut Horten Foundation, Gebert-Rüf Foundation, KTI, European Union).
In our search for FGF7-regulated genes, we identified the gene encoding the Nrf2 transcription factor. Nrf2 is a crucial regulator of the cellular stress response, since it regulates the expression of various cytoprotective proteins, including enzymes that detoxify reactive oxygen species. The analysis of Nrf2 function in tissue repair and cancer is a major emphasis of the research in our laboratory.
We demonstrated that Nrf2 expression is regulated by FGF7 (Braun et al., 2002), and activated in keratinocytes in response to electrophilic chemicals (Durchdewald et al., 2007). Functional studies revealed that Nrf2-deficiency results in prolonged wound inflammation (Braun et al., 2002), although Nrf2 in myeloid cells is dispensable for wound repair in normal mice (Joshi and Werner, 2017). We further found that Nrf transcription factors in keratinocytes are essential for skin tumor prevention (auf dem Keller et al., 2006). To determine the consequences of Nrf2 activation in the skin, we generated transgenic mice expressing a constitutively active Nrf2 mutant in keratinocytes. Activation of Nrf2 target genes strongly reduced UVB cytotoxicity through enhancement of ROS-detoxification. Remarkably, the protective effect was extended to neighbouring cells. Using different combinations of genetically modified mice we demonstrated that Nrf2 activates the production, recycling and release of glutathione and cysteine by suprabasal keratinocytes, resulting in protection of basal cells in a paracrine, glutathione/cysteine-dependent manner. These results identify Nrf2 as a key regulator in the UV response of the skin (Schäfer et al., 2010; Schäfer and Werner, 2015). However, we also showed that prolonged and excessive Nrf2 activation in keratinocytes is deleterious and results in development of an ichthyosis-like skin disease that is characterized by epidermal hyperplasia, hyperkeratosis and a defect in the epidermal barrier (Schäfer et al., 2012). This barrier function defect is likely to be further promoted by desmosomal defects. These resulted from Nrf2-mediated upregulation of microRNA-29, which targets the desmosomal component desmocollin-2 in keratinocytes (Kurinna et al., 2014). Interestingly, these studies also revealed that Nrf2 links antioxidant defense with epidermal barrier function (Schäfer et al., 2012) and with inflammatory processes (Kurinna/Muzumdar et al., 2016). We also identified an unexpected function of activated Nrf2 in the pathogenesis of chloracne (MADISH), a skin pathology that develops upon exposure to dioxin or related toxins (Schäfer et al., 2014). On the other hand, we found that Nrf2 activation ameliorates the phenotype in a mouse model of the severe genetic skin disease Netherton Syndroma (Muzumdar et al., 2020). Unfortunately, however, even mild chronic activation of Nrf2 in keratinocytes can be deleterious if the skin is affected by oncogenic mutations, resulting in a severe increase in tumor incidence and multiplicity in a mouse model of virus-induced skin tumorigenesis (Rolfs et al., 2015). Activation of Nrf2 in fibroblasts unexpectedly induced senescence of these cells, and the resulting senescence-associated secretory phenotype strongly promoted wound repair. This resulted from Nrf2-mediated upregulation of different matrix proteins and deposition of a senescence-promoting matrisome. However, the same mechanism also promoted skin cancer formation in xenograft models, revealing the bright and the dark sides of Nrf2 under different situations (Hiebert et al., 2018). The results also reveal an unexpected pro-tumorigenic activity of Nrf2 in the skin, which should be considered when Nrf2 activating compounds are used for skin protection under stress conditions.
In addition to its potent role in the skin skin, we also identified a crucial function of Nrf2 in liver regeneration through its capacity to regulate insulin/insulin-like growth factor signaling in the injured liver (Beyer et al., 2008), and we also demonstrated that Nrf2 protects from toxin-induced liver fibrosis (Xu et al., 2008). In the normal liver, we discovered a collaborative function of Nrf2 and NF-B, since combined loss of these transcription factors in hepatocytes caused severe liver inflammation and development of inflammatory hepatocellular adenomas in mice (Köhler et al., 2015). However, further activation of Nrf2 in the regenerating liver is also deleterious, since activated Nrf2 was found to regulate target genes in the regenerating liver, which enhance apoptosis and inhibit proliferation of hepatocytes (Köhler et al., 2014).
One of the targets of Nrf2 is peroxiredoxin 6, an enzyme, which detoxifies hydrogen peroxide and organic peroxides. We demonstrated that peroxiredoxin 6 is strongly expressed in the hyperproliferative epidermis of skin wounds and of psoriatic lesions (Frank et al., 1997; Munz et al., 1997). These high levels of peroxiredoxin 6 are likely to be biologically important, since overexpression of this enzyme in the epidermis of transgenic mice enhanced wound healing in aged animals and strongly protected keratinocytes from UVB toxicity (Kümin et al., 2006). In the absence of peroxiredoxin 6, UV-induced cell damage in the epidermis was strongly enhanced, confirming the important protective function of this enzyme for keratinocytes. In addition, peroxiredoxin 6 was found to be crucial for blood vessel integrity in wounded skin (Kümin et al., 2007). We also identified an important dual function of peroxiredoxin 6 in skin carcinogenesis: protection from skin tumor development, but enhancement of the malignant progression of existing tumors (Rolfs et al., 2013). Another target of Nrf2 is Gclc, the rate-limiting enzyme in the biosynthesis of the tripeptide antioxidant glutathione. Using Gclc knockout mice we demonstrated that a glutathione-Nrf2-thioredoxin cross-talk ensures keratinocyte survival and efficient wound repair (Telorack et al., 2016).
In contrast to the well-characterized Nrf2, little is known about the biological functions and mechanisms of action of the related Nrf3 transcription factor. We recently identified Nrf3 is an important regulator of the UV response of the skin. Thus, Nrf3 promotes UV-induced keratinocyte apoptosis through the regulation of cell-cell and in particular cell-matrix adhesion (Siegenthaler/Defila et al., 2018).
- Dr. Maya Ben Yehuda Greenwald () (from Israel)
- Selina Gurri ()
- Dr. Paul Hiebert () (from Canada)
- Michael Koch () (from Germany
- Dr. Andrii Kuklin () (from Ukraine)
- Prof. Dr. Ulrich auf dem Keller () (from Germany)
- Nadja Bain () (from Switzerland)
- Dr. Tobias Beyer () (from Switzerland)
- Dr. Susanne Braun () (from Germany)
- Dr. Philippe Bugnon () (from Switzerland)
- Dr. Claudia Defila () (from Switzerland)
- Dr. Sabine Dütsch () (from Switzerland)
- Dr. Nikolas Epp () (from Germany)
- Maria Gysi () (from Switzerland)
- Nicole Hallschmid (from Germany)
- Hayley Hiebert (from Canada)
- Dr. Christine Huber (Hanselmann) () (from Germany)
- Natasha Joshi (joshi.natasha@gmail-com) (from India)
- Sukalp Muzumdar () (from India)
- Dr. Ulrike Köhler () (from Germany)
- Dr. Svitlana Kurinna () (from Ukraine)
- Dr. Marcus Gassmann () (from Germany)
- Dr. Heidi Kögel (from Germany)
- Dr. Angelika Lengweiler (Kümin) () (from Switzerland)
- Dr. Franziska Metzler (Lieder) () (from Germany)
- Dr. Frank Rolfs () () (from Germany)
- Dr. Christina Rycken (Siemes) () (from Germany)
- PD Dr. Matthias Schäfer ()
- Dr. Beat Siegenthaler () (from Switzerland)
- Dr. Michèle Telorack () (from Germany)
- Dr. Weihua Xu () (from China)
- Maria zubair () (from England)