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Institute of Cell Biology - Research - Group Werner - Research 
Group Werner
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Hans Eppenberger

Markus Lezzi

José Sogo

Jean-Claude Perriard

João Relvas

Lukas Sommer

Theo Wallimann

Ned Mantei

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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 reactive oxygen species in this process. In addition, we are interested in the parallels between wound healing and cancer.

Important link: Wound healing phenotypes of transgenic mice and knockout mice

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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. To achieve these goals, we use state-of-the art approaches, including functional genomics, organotypic cell culture systems, and genetically modified mice. One of the most exciting aspects 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, which orchestrate both processes, with particular emphasis 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.

Parallels between wound healing and cancer:

Parallels between wound healing and cancer:
Parallels between wound healing and cancer:

From: M. Schäfer and S. Werner. Cancer as an overhealing wound: An old hypothesis revisited. Nat. Rev. Mol. Cell Biol. 9: 628-638.



Cited References from our laboratory can be found under “Publications”.

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Project 1:   
Fibroblast growth factors in tissue repair and cytoprotection (currently and previously funded by ETH Zürich, Swiss National Science Foundation, Roche Foundation, Deutsche Forschungsgemeinschaft)

Current co-workers:

Former co-workers:

Fibroblast growth factors (FGFs) comprise a family of 22 different mitogens, 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). KGF is a secreted protein, which is produced by various types of mesenchymal cells and by gd T cells, but not by epithelial cells. However, most types of epithelial cells express FGFR2-IIIb, the only known high-affinity receptor for KGF. KGF/FGF7 is weakly expressed in normal skin, but strikingly upregulated in dermal fibroblasts after skin injury (Werner et al., 1992). By contrast, FGFR2-IIIb is expressed on keratinocytes of the epidermis and the hair follicles, suggesting that dermis-derived KGF stimulates wound reepithelialization in a paracrine manner. This hypothesis was supported by the wound healing phenotype seen in transgenic mice, which express a dominant-negative FGFR2-IIIb mutant in the basal keratinocytes of the epidermis. These animals had a severe delay in wound reepithelialization, demonstrating the importance of KGF receptor signaling during cutaneous wound repair (Werner et al., 1994). In analogy to this finding, we also found a crucial role of FGFR signaling in liver regeneration (Steiling et al., 2003; collaboration with Prof. Christian Trautwein, Aachen), and in the pathogenesis of liver fibrosis and cirrhosis (Steiling et al., 2004; collaboration with PD Dr. Claus Hellerbrand, University of Regensburg).

Surprisingly, results from another laboratory demonstrated that mice lacking KGF/FGF7 show normal healing of incisional skin wounds, suggesting that other FGFR2-IIIb ligands can compensate for the lack of KGF. The most likely candidate for such a compensatory effect is FGF10, since this FGF family member is (i) highly homologous to KGF/FGF7, (ii) co-expressed with KGF/FGF7 in adult mouse tissues (Beer et al., 1997), and (iii) a high-affinity ligand of FGFR2-IIIb (Beer et al., 2000, and others). In addition, FGF10 binds and activates a splice variant of FGFR1 (FGFR1-IIIb), which is also expressed on keratinocytes (Beer et al., 2000). A second homologue of KGF/FGF7, FGF22, is also expressed in normal and wounded skin (Beyer et al., 2003). Recent studies revealed crucial roles of these FGFR2-IIIb ligands in skin morphogenesis and homeostasis, since mice lacking this receptor in the epidermis have severe skin abnormalities and they are more susceptible to skin carcinogenesis (Grose et al., 2007). However, the roles of other FGF receptors in the skin remain to be determined, and the mechanisms of FGF action in keratinocytes need to be further explored. These questions are currently being addressed in our laboratory.

To gain insight into the mechanisms of KGF/FGF7 and FGF10 action in normal and wounded skin we searched for genes, which are regulated by these factors in cultured keratinocytes. The identified genes help to explain how KGF/FGF7 mediates various processes in normal and wounded skin, such as keratinocyte proliferation and migration, and indirect effects such as angiogenesis and stimulation of matrix deposition. Some of these genes and their products have been characterized in our laboratory with regard to their roles in skin morphogenesis and tissue repair. These include the matrix metalloproteinase stromelysin-2, which regulates keratinocyte migration and organization in wounded skin (Madlener et al., 1996; Madlener and Werner, 1997; Madlener et al., 1998; Krampert et al., 2004) as well as vascular endothelial growth factor, which regulates angiogenesis (Frank et al., 1995).

In addition to its potent effect on epithelial cell proliferation and migration, KGF/FGF7 exerts potent cytoprotective activities. This may also be important in injured organs, in particular under stress conditions. Thus, KGF can protect intestinal epithelial cells from cell death induced by radiation and chemotherapy, and it has recently been approved for the treatment of mucositis in cancer patients. These severe oral and intestinal lesions are a major side effect of high dose radiation- and chemotherapy. In our studies, we confirmed the cytoprotective effect of KGF/FGF7 for the skin, and we demonstrated that KGF/FGF7 protects keratinocytes in vitro and in vivo from UV- or toxin-induced cell death. As the underlying mechanism we identified a KGF-regulated expression of various genes involved in the control of the cellular redox homeostasis. These include the Nrf2 transcription factor as well as peroxiredoxin 6. These proteins are currently characterized in our laboratory with regard to their functions in tissue repair, inflammatory disease and cancer (see project 3).

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Project 2:     
Activin: A novel player in inflammation and repair (currently and previously funded by ETH Zürich, Swiss National Science Foundation, European Community, Deutsche Forschungsgemeinschaft, EMBO, Oncosuisse, Boehringer Ingelheim Fonds)

Current co-workers:

Former co-workers:

Activins are members the TGF-b superfamily of growth and differentiation factors, which influence proliferation and differentiation of many different cell types. In our work, we demonstrated important roles of activin in skin homeostasis and repair. Thus, we found a strikingly increased expression of activin in the granulation tissue and in suprabasal keratinocytes of the hyperproliferative epithelium after skin injury (Hubner et al., 1996). Furthermore, all known activin receptors were expressed in the mesenchymal and epithelial compartments of normal and wounded skin, although their expression did not change after injury. These results suggested a dual function of activin in the granulation tissue and also in the differentiating keratinocytes.

To determine the activities of activin in the skin, we overexpressed activin in the basal keratinocytes of the epidermis of transgenic mice. These animals had significant abnormalities in the skin, including epidermal hyperplasia as a result of enhanced keratinocyte proliferation and abnormal differentiation as well as a fibrotic dermis (Munz et al., 1999). Furthermore, hair follicle morphogenesis and cycling were affected in these animals (Nakamura et al., 2003; collaboration with Prof. Ralf Paus, University of Hamburg). The most striking finding was the strong enhancement of the wound healing process in the activin-overexpressing mice, whereby granulation tissue formation was particularly stimulated (Munz et al., 1999). However, we also found enhanced scarring in these animals.

To determine the role of endogenous activin in skin morphogenesis and wound repair, we inhibited activin in the skin by overexpression of the activin antagonist follistatin in the epidermis of transgenic mice. Interestingly, these mice had the opposite phenotype compared to the activin-overexpressing mice. The wound healing process was strongly enhanced, but the quality of the residual scar tissue was improved (Wankell et al., 2001). In addition, these mice suffer from severe abnormalities in tooth development (Wang et al., 2004a and b; collaboration with Prof. Irma Thesleff, University of Helsinki), and the number of Langerhans cells in the epidermis of these mice is strongly reduced (Stoitzner et al., 2005; collaboration with Dr. Nikolaus Romani, University of Innsbruck).

Taken together, these results provide evidence for an important role of activin in wound repair as well as in keratinocyte differentiation, dermal fibrosis, and possibly also in human skin disease. Current studies aim at the elucidation of the mechanisms of activin action. For example, we recently found that the effect of activin on the wound repair process is mediated via keratinocytes and stromal cells and that the effect of activin on keratinocytes is dose-dependent in vivo (Bamberger et al., 2005). Furthermore, we demonstrated that limited activation of activin in the epidermis through the loss of keratinocyte-derived follistatin enhances wound reepithelialization without increasing the scarring response (Antsiferova et al., 2009).

To gain insight into the mechanisms of activin action in keratinocytes, we searched for genes that are regulated by this growth and differentiation factor in cultured keratinocytes. Interestingly, the identified genes are predominantly involved in the regulation of keratinocyte differentiation and migration, suggesting that these are the major functions of activin in keratinocytes (Werner et al., 2001; Rotzer et al., 2006). By contrast, TGF-b regulates a wide variety of genes in keratinocytes, indicating that it has a broader function in keratinocytes compared to activin (Werner et al., 2000; 2001; Krampert et al., 2005). The activin target genes are currently being characterized with regard to their role in keratinocyte differentiation and wound repair.

Role of transcriptional regulators in tissue repair, inflammatory disease and cancer (currently and previously funded by ETH Zürich, Swiss National Science Foundation, Boehringer Ingelheim Fonds, Deutsche Forschungsgemeinschaft, AETAS Foundation, EMBO, UBS Foundation, Studienstiftung des Deutschen Volkes)

Role of transcriptional regulators in tissue repair, inflammatory disease and cancer (currently and previously funded by ETH Zürich, Swiss National Science Foundation, Boehringer Ingelheim Fonds, Deutsche Forschungsgemeinschaft, AETAS Foundation, EMBO, UBS Foundation, Studienstiftung des Deutschen Volkes)

Role of transcriptional regulators in tissue repair, inflammatory disease and cancer (currently and previously funded by ETH Zürich, Swiss National Science Foundation, Boehringer Ingelheim Fonds, Deutsche Forschungsgemeinschaft, AETAS Foundation, EMBO, UBS Foundation, Studienstiftung des Deutschen Volkes)

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). Thus we have shown a strong over-expression of activin in affected areas of patients suffering from inflammatory bowel disease (Hubner et al., 1997) and from gastric ulcers (Becker et al., 2003; collaboration with Dr. T. Pohle, University of Münster). Finally, in collaboration with the laboratory of Prof. Christian Alzheimer at the University of Kiel we demonstrated a novel and important role of activin in neuroprotection, synaptic plasticity and anxiety (Tretter et al., 1996; Tretter et al., 2000; Müller et al., 2006, Tseng et al., 2008). We are currently studying the mechanisms of activin action in this process.
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Project 3:     

Role of transcriptional regulators in tissue repair, inflammatory disease and cancer (currently and previously funded by ETH Zürich, Swiss National Science Foundation, Boehringer Ingelheim Fonds, Deutsche Forschungsgemeinschaft, AETAS Foundation, EMBO, UBS Foundation, Studienstiftung des Deutschen Volkes)

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 recently demonstrated that Nrf2 expression is regulated by FGF7 in vitro and most likely also in vivo (Braun et al., 2002). It is activated in keratinocytes in response to electrophilic chemicals (Durchdewald et al., 2007). We found that Nrf2 regulates inflammation and gene expression in wounded skin (Braun et al., 2002), and that Nrf transcription factors in keratinocytes are essential for skin tumor prevention (auf dem Keller et al., 2006). In addition, we recently identified a crucial role 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).
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).
In addition to Nrf2, we recently characterized the role of the serum response factor (SRF) in the skin in collaboration with the laboratory of Prof. Alfred Nordheim, University of Tübingen. We demonstrated that loss of SRF in keratinocytes results in hyperproliferative skin disease in mice. This was caused by disruption of the cytoskeleton, resulting in a defect in cell-cell contacts and subsequent impairments of the epidermal barrier function. As a consequence, an inflammatory response was initiated and the mice developed skin lesions resembling those seen in the inflammatory skin disease psoriasis. Most interestingly, we also found a loss of SRF in keratinocytes of patients suffering from psoriasis, suggesting a causative role of the loss of this transcription factor in the pathogenesis of psoriasis (Kögel et al., 2009).

Current co-workers:

Former co-workers:

 

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