Publications by authors named "Sabine Werner"

191 Publications

NEDD4-1 is a key regulator of epidermal homeostasis and wound repair.

J Invest Dermatol 2021 Oct 28. Epub 2021 Oct 28.

Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland. Electronic address:

The ubiquitin ligase Nedd4-1 plays key roles in organ development, tissue homeostasis and cancer, but its functions in the skin are largely unknown. Here we show perturbations in keratinocyte proliferation and terminal differentiation, epidermal barrier function, and hair follicle cycling as well as increased UV-induced apoptosis in mice lacking Nedd4-1 in keratinocytes. In particular, re-epithelialization of full-thickness excisional wounds was delayed in the mutant mice. This was caused by severely impaired migration and proliferation of Nedd4-1-deficient keratinocytes. Therefore, a few keratinocytes, which had escaped recombination and expressed Nedd4-1, obtained a growth advantage and contributed to re-epithelialization. Mechanistically, Nedd4-1-deficient keratinocytes failed to efficiently activate the Erk1/2 mitogen-activated kinases and the YAP transcriptional co-activator. These results identify Nedd4-1 as an essential player in wound repair through its effect on mitogenic and motogenic signaling pathways in keratinocytes.
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http://dx.doi.org/10.1016/j.jid.2021.09.033DOI Listing
October 2021

Fibroblast growth factor receptor 3 in hepatocytes protects from toxin-induced liver injury and fibrosis.

iScience 2021 Oct 16;24(10):103143. Epub 2021 Sep 16.

Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland.

The liver's remarkable regenerative capacity is orchestrated by several growth factors and cytokines. Fibroblast growth factor receptor 3 (Fgfr3) is frequently overexpressed in hepatocellular carcinoma and promotes cancer aggressiveness, whereas its role in liver homeostasis, repair and regeneration is unknown. We show here that Fgfr3 is expressed by hepatocytes in the healthy liver. Its major ligand, Fgf9, is mainly expressed by non-parenchymal cells and upregulated upon injury. Mice lacking Fgfr3 in hepatocytes exhibit increased tissue necrosis after acute toxin treatment and more excessive fibrosis after long-term injury. This was not a consequence of immunological alterations in the non-injured liver as revealed by comprehensive flow cytometry analysis. Rather, loss of Fgfr3 altered the expression of metabolic and pro-fibrotic genes in hepatocytes. These results identify a paracrine Fgf9-Fgfr3 signaling pathway that protects from toxin-induced cell death and the resulting liver fibrosis and suggests a potential use of FGFR3 ligands for therapeutic purposes.
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http://dx.doi.org/10.1016/j.isci.2021.103143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497853PMC
October 2021

Acute and chronic effects of a light-activated FGF receptor in keratinocytes in vitro and in mice.

Life Sci Alliance 2021 11 21;4(11). Epub 2021 Sep 21.

Department of Biology, Institute of Molecular Health Sciences, Eidgenössische Technische Hochschule (ETH) Zurich, Zurich, Switzerland

FGFs and their high-affinity receptors (FGFRs) play key roles in development, tissue repair, and disease. Because FGFRs bind overlapping sets of ligands, their individual functions cannot be determined using ligand stimulation. Here, we generated a light-activated FGFR2 variant (OptoR2) to selectively activate signaling by the major FGFR in keratinocytes. Illumination of OptoR2-expressing HEK 293T cells activated FGFR signaling with remarkable temporal precision and promoted cell migration and proliferation. In murine and human keratinocytes, OptoR2 activation rapidly induced the classical FGFR signaling pathways and expression of FGF target genes. Surprisingly, multi-level counter-regulation occurred in keratinocytes in vitro and in transgenic mice in vivo, including OptoR2 down-regulation and loss of responsiveness to light activation. These results demonstrate unexpected cell type-specific limitations of optogenetic FGFRs in long-term in vitro and in vivo settings and highlight the complex consequences of transferring optogenetic cell signaling tools into their relevant cellular contexts.
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http://dx.doi.org/10.26508/lsa.202101100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473723PMC
November 2021

Long-Term Imaging of Wound Angiogenesis with Large Scale Optoacoustic Microscopy.

Adv Sci (Weinh) 2021 07 2;8(13):2004226. Epub 2021 May 2.

Institute for Biomedical Engineering and Institute of Pharmacology and Toxicology Faculty of Medicine University of Zurich Zurich 8057 Switzerland.

Wound healing is a well-coordinated process, necessitating efficient formation of new blood vessels. Vascularization defects are therefore a major risk factor for chronic, non-healing wounds. The dynamics of mammalian tissue revascularization, vessel maturation, and remodeling remain poorly understood due to lack of suitable in vivo imaging tools. A label-free large-scale optoacoustic microscopy (LSOM) approach is developed for rapid, non-invasive, volumetric imaging of tissue regeneration over large areas spanning up to 50 mm with a depth penetration of 1.5 mm. Vascular networks in dorsal mouse skin and full-thickness excisional wounds are imaged with capillary resolution during the course of healing, revealing previously undocumented views of the angiogenesis process in an unperturbed wound environment. Development of an automatic analysis framework enables the identification of key features of wound angiogenesis, including vessel length, diameter, tortuosity, and angular alignment. The approach offers a versatile tool for preclinical research in tissue engineering and regenerative medicine, empowering label-free, longitudinal, high-throughput, and quantitative studies of the microcirculation in processes associated with normal and impaired vascular remodeling, and analysis of vascular responses to pharmacological interventions in vivo.
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http://dx.doi.org/10.1002/advs.202004226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261523PMC
July 2021

Imaging and targeting LOX-mediated tissue remodeling with a reactive collagen peptide.

Nat Chem Biol 2021 08 12;17(8):865-871. Epub 2021 Jul 12.

Laboratory of Organic Chemistry, ETH Zurich, Zurich, Switzerland.

Collagens are fibrous proteins that are integral to the strength and stability of connective tissues. During collagen maturation, lysyl oxidases (LOX) initiate the cross-linking of fibers, but abnormal LOX activity is associated with impaired tissue function as seen in fibrotic and malignant diseases. Visualizing and targeting this dynamic process in healthy and diseased tissue is important, but so far not feasible. Here we present a probe for the simultaneous monitoring and targeting of LOX-mediated collagen cross-linking that combines a LOX-activity sensor with a collagen peptide to chemoselectively target endogenous aldehydes generated by LOX. This synergistic probe becomes covalently anchored and lights up in vivo and in situ in response to LOX at the sites where cross-linking occurs, as demonstrated by staining of normal skin and cancer sections. We anticipate that our reactive collagen-based sensor will improve understanding of collagen remodeling and provide opportunities for the diagnosis of fibrotic and malignant diseases.
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http://dx.doi.org/10.1038/s41589-021-00830-6DOI Listing
August 2021

Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis.

Nucleic Acids Res 2021 04;49(7):3748-3763

Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland.

Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2 and p63- a key player in epithelial morphogenesis. Chromatin immunoprecipitation combined with sequencing and reporter assays identifies enhancers and promoters that are simultaneously activated by NRF2 and p63 in human keratinocytes. Modeling of p63 and NRF2 binding to nucleosomal DNA suggests their chromatin-assisted interaction. Pharmacological and genetic activation of NRF2 increases NRF2-p63 binding to enhancers and promotes keratinocyte proliferation, which involves the common NRF2-p63 target cyclin-dependent kinase 12. These results unravel a collaborative function of NRF2 and p63 in the control of epidermal renewal and suggest their combined activation as a strategy to promote repair of human skin and other stratified epithelia.
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http://dx.doi.org/10.1093/nar/gkab167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053124PMC
April 2021

Exosomes for Wound Healing: Purification Optimization and Identification of Bioactive Components.

Adv Sci (Weinh) 2020 Dec 27;7(23):2002596. Epub 2020 Oct 27.

Institute of Pharmaceutical Sciences Department of Chemistry and Applied Biosciences ETH Zurich Zurich 8093 Switzerland.

Human mesenchymal stem cell exosomes have been shown to promote cutaneous wound healing. Their bioactivity is most often attributed to their protein and nucleic acid components, while the function of exosomal lipids remains comparatively unexplored. This work specifically assesses the involvement of lipids and the transmembrane enzyme CD73 in the exosomes' biological activity in stimulating the cutaneous wound healing process. Since exosome preparation processes are not harmonized yet, certain production and purification parameters are first systematically investigated, enabling the optimization of a standardized protocol delivering high exosome integrity, yield, and purity. An in situ enzymatic assay is introduced to specifically assess the vesicle functionality, and quantitative proteomics is employed to establish the cell culture conditions yielding a stable exosome protein profile. Using a combination of in vitro approaches, CD73 and constitutional lipids of HPV-16 E6/E7 transformed human bone marrow stromal cell-derived exosomes are identified as key bioactive components promoting the exosome-driven acceleration of processes required for wound repair. A pilot wound healing study in mice indeed suggests a role of lipids in the exosomes' biological activity. Strikingly, the extent of the bioactivity of these exosomal components is found to be dependent on the target cell type.
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http://dx.doi.org/10.1002/advs.202002596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709981PMC
December 2020

Genotoxic Agents: An Unexpected Effect on Healthy Epithelia.

Dev Cell 2020 12;55(5):515-517

Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland. Electronic address:

DNA cross-linking agents are common chemotherapeutics for cancer treatment, but their effect on normal cells is largely unknown. In this issue of Developmental Cell, Seldin and Macara (2020) show that such compounds induce epithelial hyperplasia and stem cell fate mis-specification in a non-cell-autonomous manner via inflammasome activation in dermal fibroblasts.
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http://dx.doi.org/10.1016/j.devcel.2020.11.001DOI Listing
December 2020

Wound Repair, Scar Formation, and Cancer: Converging on Activin.

Trends Mol Med 2020 12 30;26(12):1107-1117. Epub 2020 Aug 30.

Institute of Molecular Health Sciences, ETH Zurich, Honggerberg, HPL F12, Otto-Stern-Weg 7, 8093 Zurich, Switzerland. Electronic address:

Wound repair is a highly regulated process that requires the interaction of various cell types. It has been shown that cancers use the mechanisms of wound healing to promote their own growth. Therefore, it is of importance to identify common regulators of wound repair and tumor formation and to unravel their functions and mechanisms of action. An exciting example is activin, which acts on multiple cell types in wounds and tumors, thereby promoting healing, but also scar formation and tumorigenesis. Here, we summarize current knowledge on the role of activin in these processes and highlight the therapeutic potential of activin or activin antagonists for the treatment of impaired healing or excessive scarring and cancer, respectively.
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http://dx.doi.org/10.1016/j.molmed.2020.07.009DOI Listing
December 2020

Antagonism of interferon signaling by fibroblast growth factors promotes viral replication.

EMBO Mol Med 2020 09 27;12(9):e11793. Epub 2020 Jul 27.

Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

Fibroblast growth factors (FGFs) play key roles in the pathogenesis of different human diseases, but the cross-talk between FGFs and other cytokines remains largely unexplored. We identified an unexpected antagonistic effect of FGFs on the interferon (IFN) signaling pathway. Genetic or pharmacological inhibition of FGF receptor signaling in keratinocytes promoted the expression of interferon-stimulated genes (ISG) and proteins in vitro and in vivo. Conversely, FGF7 or FGF10 treatment of keratinocytes suppressed ISG expression under homeostatic conditions and in response to IFN or poly(I:C) treatment. FGF-mediated ISG suppression was independent of IFN receptors, occurred at the transcriptional level, and required FGF receptor kinase and proteasomal activity. It is not restricted to keratinocytes and functionally relevant, since FGFs promoted the replication of herpes simplex virus I (HSV-1), lymphocytic choriomeningitis virus, and Zika virus. Most importantly, inhibition of FGFR signaling blocked HSV-1 replication in cultured human keratinocytes and in mice. These results suggest the use of FGFR kinase inhibitors for the treatment of viral infections.
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http://dx.doi.org/10.15252/emmm.201911793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507082PMC
September 2020

The commensal skin microbiota triggers type I IFN-dependent innate repair responses in injured skin.

Nat Immunol 2020 09 13;21(9):1034-1045. Epub 2020 Jul 13.

Department of Dermatology, CHUV University Hospital, University of Lausanne, Lausanne, Switzerland.

Skin wounds heal by coordinated induction of inflammation and tissue repair, but the initiating events are poorly defined. Here we uncover a fundamental role of commensal skin microbiota in this process and show that it is mediated by the recruitment and the activation of type I interferon (IFN)-producing plasmacytoid DC (pDC). Commensal bacteria colonizing skin wounds trigger activation of neutrophils to express the chemokine CXCL10, which recruits pDC and acts as an antimicrobial protein to kill exposed microbiota, leading to the formation of CXCL10-bacterial DNA complexes. These complexes and not complexes with host-derived DNA activate pDC to produce type I IFNs, which accelerate wound closure by triggering skin inflammation and early T cell-independent wound repair responses, mediated by macrophages and fibroblasts that produce major growth factors required for healing. These findings identify a key function of commensal microbiota in driving a central innate wound healing response of the skin.
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http://dx.doi.org/10.1038/s41590-020-0721-6DOI Listing
September 2020

A Dual-Acting Nitric Oxide Donor and Phosphodiesterase 5 Inhibitor Promotes Wound Healing in Normal Mice and Mice with Diabetes.

J Invest Dermatol 2021 02 27;141(2):415-426. Epub 2020 Jun 27.

Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland. Electronic address:

Chronic wounds affect a large percentage of the population worldwide and cause significant morbidity. Unfortunately, efficient compounds for the treatment of chronic wounds are yet not available. Endothelial dysfunction, which is at least in part a result of compromised nitric oxide production and concomitant reduction in cGMP levels, is a major pathologic feature of chronic wounds. Therefore, we designed and synthesized a compound with a unique dual-acting activity (TOP-N53), acting as a nitric oxide donor and phosphodiesterase 5 inhibitor, and applied it locally to full-thickness skin wounds in healthy and healing-impaired mice with diabetes. TOP-N53 promoted keratinocyte proliferation, angiogenesis, and collagen maturation in healthy mice without accelerating the wound inflammatory response or scar formation. Most importantly, it partially rescued the healing impairment of mice with genetically determined type II diabetes (db/db) by stimulating re-epithelialization and granulation tissue formation, including angiogenesis. In vitro studies with human and murine primary cells showed a positive effect of TOP-N53 on keratinocyte and fibroblast migration, keratinocyte proliferation, and endothelial cell migration and tube formation. These results demonstrate a remarkable healing-promoting activity of TOP-N53 by targeting the major resident cells in the wound tissue.
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http://dx.doi.org/10.1016/j.jid.2020.05.111DOI Listing
February 2021

Genetic activation of Nrf2 reduces cutaneous symptoms in a murine model of Netherton syndrome.

Dis Model Mech 2020 06 1;13(5). Epub 2020 Jun 1.

Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, 8093 Zurich, Switzerland

Netherton syndrome is a monogenic autosomal recessive disorder primarily characterized by the detachment of the uppermost layer of the epidermis, the It results from mutations in the gene, which codes for a kallikrein inhibitor. Uncontrolled kallikrein activity leads to premature desquamation, resulting in a severe epidermal barrier defect and subsequent life-threatening systemic infections and chronic cutaneous inflammation. Here, we show that genetic activation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nfe2l2/Nrf2) in keratinocytes of knockout mice, a model for Netherton syndrome, significantly alleviates their cutaneous phenotype. Nrf2 activation promoted attachment of the and concomitant epidermal barrier function, and reduced the expression of pro-inflammatory cytokines such as tumor necrosis factor α and thymic stromal lymphopoietin. Mechanistically, we show that Nrf2 activation induces overexpression of secretory leukocyte protease inhibitor (Slpi), a known inhibitor of kallikrein 7 and elastase 2, in mouse and human keratinocytes and , respectively. In the Spink5-deficient epidermis, the upregulation of Slpi is likely to promote stabilization of corneodesmosomes, thereby preventing premature desquamation. Our results suggest pharmacological NRF2 activation as a promising treatment modality for Netherton syndrome patients.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/dmm.042648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286291PMC
June 2020

Activin-mediated alterations of the fibroblast transcriptome and matrisome control the biomechanical properties of skin wounds.

Nat Commun 2020 05 25;11(1):2604. Epub 2020 May 25.

Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Otto-Stern-Weg 7, 8093, Zurich, Switzerland.

Matrix deposition is essential for wound repair, but when excessive, leads to hypertrophic scars and fibrosis. The factors that control matrix deposition in skin wounds have only partially been identified and the consequences of matrix alterations for the mechanical properties of wounds are largely unknown. Here, we report how a single diffusible factor, activin A, affects the healing process across scales. Bioinformatics analysis of wound fibroblast transcriptome data combined with biochemical and histopathological analyses of wounds and functional in vitro studies identify that activin promotes pro-fibrotic gene expression signatures and processes, including glycoprotein and proteoglycan biosynthesis, collagen deposition, and altered collagen cross-linking. As a consequence, activin strongly reduces the wound and scar deformability, as identified by a non-invasive in vivo method for biomechanical analysis. These results provide mechanistic insight into the roles of activin in wound repair and fibrosis and identify the functional consequences of alterations in the wound matrisome at the biomechanical level.
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http://dx.doi.org/10.1038/s41467-020-16409-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248062PMC
May 2020

Comprehensive characterization of myeloid cells during wound healing in healthy and healing-impaired diabetic mice.

Eur J Immunol 2020 09 13;50(9):1335-1349. Epub 2020 May 13.

Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, Zurich, Switzerland.

Wound healing involves the concerted action of various lymphoid and in particular myeloid cell populations. To characterize and quantitate different types of myeloid cells and to obtain information on their kinetics during wound healing, we performed multiparametric flow cytometry analysis. In healthy mice, neutrophil numbers increased early after injury and returned to near basal levels after completion of healing. Macrophages, monocyte-derived dendritic cells (DCs), and eosinophils were abundant throughout the healing phase, in particular in early wounds, and Langerhans cells increased after wounding and remained elevated after epithelial closure. Major differences in healing-impaired diabetic mice were a much higher percentage of immune cells in late wounds, mainly as a result of neutrophil, macrophage, and monocyte persistence; reduced numbers and percentages of macrophages and monocyte-derived DCs in early wounds; and of Langerhans cells, conventional DCs, and eosinophils throughout the healing process. Finally, unbiased cluster analysis (PhenoGraph) identified a large number of different clusters of myeloid cells in skin wounds. These results provide insight into myeloid cell diversity and dynamics during wound repair and highlight the abnormal inflammatory response associated with impaired healing.
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http://dx.doi.org/10.1002/eji.201948438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496577PMC
September 2020

The aptamer BC 007 for treatment of dilated cardiomyopathy: evaluation in Doberman  Pinschers of efficacy and outcomes.

ESC Heart Fail 2020 06 24;7(3):844-855. Epub 2020 Mar 24.

Department of Cardiology, Clinic of Small Animal Medicine, Ludwig-Maximilians-University, Munich, Germany.

Aims: Aptamer BC 007, a 15-mer single-strand DNA oligonucleotide (5'-GGTTGGTGTGGTTGG-3'), was developed to neutralize functional autoantibodies that bind to the extracellular domains of G protein-coupled receptors (GPCR-AAB), leading to the modulation of receptor-mediated signalling cascades that induce pathophysiological states. Among the GPCR-AAB, there are those directed against the β1-adrenergic receptor (β1-AAB) that are highly present in patients with dilated cardiomyopathy (DCM) and are increasingly accepted as disease drivers. Using Doberman Pinschers (DP) with DCM, which possess similarities with human DCM among these β1-AAB positivity for that the disease-driving role in DP DCM was demonstrated, the safety of BC 007, efficacy for neutralizing β1-AAB, and the DP's outcome were investigated.

Methods And Results: Fourteen client-owned β1-AAB-positive DP with electrocardiographically and echocardiographically indicated DCM were treated with BC 007. For controlling, two groups were created: 14 β1-AAB-positive DP with DCM not treated with BC 007 (Control 1) and 14 DP with DCM closely matched to the BC 007-treated DP (Control 2), retrospectively selected from the institutional database of DP. After treatment, DP were monitored both echocardiographically, and for β1-AAB, and survival curves were calculated. Based on clinical and laboratory examination, no adverse effects associated with BC 007 treatment were observed during the study. Forty-eight hours after treatment, the DP's blood was free of β1-AAB, which led to a reduction or stabilization of left ventricular end-systolic volume (ESVI) during β1-AAB free time in 10 of the treated DP. In one DP, where β1-AAB returned after 3 months and ESVI worsened again, a second BC 007 treatment after 9 months again cleared the blood from β1-AAB and improved the ESVI. Compared with the controls, DP treated with BC 007 showed a significantly longer survival time [572 days, interquartile range (IQR) 442-840 days] vs. Control group 1 (266 days, IQR 97-438 days; logrank: P = 0.009) and Control group 2 (229 days, IQR 174-319 days; logrank: P = 0.012).

Conclusions: Treatment with BC 007 for β1-AAB neutralization was safe, resulted in a long-lasting reduction of β1-AAB combined with improved cardiac function and prolonged the survival of DP with DCM. Using a natural large animal model of DCM considered superior to small animal models of immunization-induced cardiomyopathy, combined with a study design comparable with clinical trials, we believe that our results provide the basis for optimism that treatment with BC 007 might also be effective in human patients with DCM.
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http://dx.doi.org/10.1002/ehf2.12628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261533PMC
June 2020

A paracrine activin A-mDia2 axis promotes squamous carcinogenesis via fibroblast reprogramming.

EMBO Mol Med 2020 04 9;12(4):e11466. Epub 2020 Mar 9.

Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

Cancer-associated fibroblasts (CAFs) are key regulators of tumorigenesis and promising targets for next-generation therapies. We discovered that cancer cell-derived activin A reprograms fibroblasts into pro-tumorigenic CAFs. Mechanistically, this occurs via Smad2-mediated transcriptional regulation of the formin mDia2, which directly promotes filopodia formation and cell migration. mDia2 also induces expression of CAF marker genes through prevention of p53 nuclear accumulation, resulting in the production of a pro-tumorigenic matrisome and secretome. The translational relevance of this finding is reflected by activin A overexpression in tumor cells and of mDia2 in the stroma of skin cancer and other malignancies and the correlation of high activin A/mDia2 levels with poor patient survival. Blockade of this signaling axis using inhibitors of activin, activin receptors, or mDia2 suppressed cancer cell malignancy and squamous carcinogenesis in 3D organotypic cultures, ex vivo, and in vivo, providing a rationale for pharmacological inhibition of activin A-mDia2 signaling in stratified cancer patients.
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http://dx.doi.org/10.15252/emmm.201911466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136968PMC
April 2020

Tussilagonone Ameliorates Psoriatic Features in Keratinocytes and Imiquimod-Induced Psoriasis-Like Lesions in Mice via NRF2 Activation.

J Invest Dermatol 2020 06 23;140(6):1223-1232.e4. Epub 2019 Dec 23.

Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, South Korea; CHD Medics Co, Goyang, Gyeonggi, South Korea. Electronic address:

Psoriasis is a common inflammatory skin disorder that is characterized by keratinocyte hyperproliferation and abnormal differentiation, resulting in the thickening of the epidermis and stratum corneum. In this study, we investigated in vitro and in vivo pharmacological effects of tussilagonone (TGN), a sesquiterpenoid isolated from Tussilago farfara, on transcription factors relevant for the pathogenesis of psoriasis. TGN inhibited activation of NF-κB and STAT3, leading to the attenuated expression of psoriasis-related inflammatory genes and suppression of keratinocyte hyperproliferation. Mechanistically, we show that the inhibition of NF-κB and STAT3 by TGN is mediated through activation of the cytoprotective transcription factor NRF2. Evaluation of in vivo antipsoriatic effects of topical TGN in the imiquimod-induced psoriasis-like dermatitis mouse model demonstrated amelioration of imiquimod-induced phenotypical changes, lesion severity score, epidermal thickening, and reduction in dermal cellularity. The spleen index also diminished in TGN-treated mice, suggesting anti-inflammatory properties of TGN. Moreover, TGN significantly attenuated the imiquimod-induced mRNA levels of psoriasis-associated inflammatory cytokines and antimicrobial peptides and reduced epidermal hyperproliferation. Taken together, TGN, as a potent NRF2 activator, is a promising therapeutic candidate for the development of antipsoriatic agents derived from medicinal plants.
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http://dx.doi.org/10.1016/j.jid.2019.12.008DOI Listing
June 2020

Mouse genetics identifies unique and overlapping functions of fibroblast growth factor receptors in keratinocytes.

J Cell Mol Med 2020 01 12;24(2):1774-1785. Epub 2019 Dec 12.

Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.

Fibroblast growth factors (FGFs) are key regulators of tissue development, homeostasis and repair, and abnormal FGF signalling is associated with various human diseases. In human and murine epidermis, FGF receptor 3 (FGFR3) activation causes benign skin tumours, but the consequences of FGFR3 deficiency in this tissue have not been determined. Here, we show that FGFR3 in keratinocytes is dispensable for mouse skin development, homeostasis and wound repair. However, the defect in the epidermal barrier and the resulting inflammatory skin disease that develops in mice lacking FGFR1 and FGFR2 in keratinocytes were further aggravated upon additional loss of FGFR3. This caused fibroblast activation and fibrosis in the FGFR1/FGFR2 double-knockout mice and even more in mice lacking all three FGFRs, revealing functional redundancy of FGFR3 with FGFR1 and FGFR2 for maintaining the epidermal barrier. Taken together, our study demonstrates that FGFR1, FGFR2 and FGFR3 act together to maintain epidermal integrity and cutaneous homeostasis, with FGFR2 being the dominant receptor.
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http://dx.doi.org/10.1111/jcmm.14871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991627PMC
January 2020

Tissue Repair: Guarding against Friendly Fire.

Curr Biol 2019 11;29(22):R1191-R1193

Institute of Molecular Health Sciences, ETH Zurich, Switzerland. Electronic address:

Following tissue injury, cells produce reactive molecules that fight off invading pathogens, but these factors might also damage the host tissue. A new study has characterized a network of defense pathways that synergize to protect cells from collateral damage and drive repair.
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http://dx.doi.org/10.1016/j.cub.2019.09.073DOI Listing
November 2019

Correction to: Nrf3 promotes UV-induced keratinocyte apoptosis through suppression of cell adhesion.

Cell Death Differ 2020 Jan;27(1):402

Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, 8093, Switzerland.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41418-019-0437-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205871PMC
January 2020

Regulation of Wound Healing by the NRF2 Transcription Factor-More Than Cytoprotection.

Int J Mol Sci 2019 Aug 8;20(16). Epub 2019 Aug 8.

Institute for Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology Zürich, 8093 Zurich, Switzerland.

The nuclear factor-erythroid 2-related factor 2 (NRF2) transcription factor plays a central role in mediating the cellular stress response. Due to their antioxidant properties, compounds activating NRF2 have received much attention as potential medications for disease prevention, or even for therapy. Accumulating evidence suggests that activation of the NRF2 pathway also has a major impact on wound healing and may be beneficial in the treatment of chronic wounds, which remain a considerable health and economic burden. While NRF2 activation indeed shows promise, important considerations need to be made in light of corresponding evidence that also points towards pro-tumorigenic effects of NRF2. In this review, we discuss the evidence to date, highlighting recent advances using gain- and loss-of-function animal models and how these data fit with observations in humans.
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http://dx.doi.org/10.3390/ijms20163856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720615PMC
August 2019

The NLRP1 Inflammasome Pathway Is Silenced in Cutaneous Squamous Cell Carcinoma.

J Invest Dermatol 2019 08 7;139(8):1788-1797.e6. Epub 2019 Feb 7.

Department of Dermatology, University Hospital Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Switzerland. Electronic address:

The inflammasome protein NLRP1 is an important innate immune sensor in human keratinocytes, and, together with ASC and caspase-1, it mediates the activation and secretion of the proinflammatory cytokines IL-1β and IL-18. These cytokines and inflammasomes can have partly opposing roles during tumorigenesis in mice. In contrast, ASC expression is impaired in different types of cancer in humans. In this study, we analyzed inflammasome activation and expression of inflammasome proteins, including their downstream cytokines, in squamous cell carcinomas, a type of nonmelanoma skin cancer derived from keratinocytes. We assessed mRNA and protein levels in human primary keratinocytes and skin carcinoma-derived SCC cell lines and detected a strong down-regulation of expression of NLRP1 inflammasome components, as well as reduced expression of the proinflammatory cytokines proIL-1β and proIL-1α. Protein levels of NLRP1, ASC, caspase-1, and proIL-1β were reduced in patient-derived SCC biopsy samples compared with healthy skin. Furthermore, the results suggest that expression of PYCARD (ASC), CASP1, IL1B, and NLRP1 is silenced by methylation in SCC cell lines. In conclusion, the down-regulation of the inflammasome pathway in SCCs might favor late tumor development in human skin.
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http://dx.doi.org/10.1016/j.jid.2019.01.025DOI Listing
August 2019

Nrf2-Mediated Expansion of Pilosebaceous Cells Accelerates Cutaneous Wound Healing.

Am J Pathol 2019 03 26;189(3):568-579. Epub 2018 Dec 26.

Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland. Electronic address:

The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor is a key regulator of the cellular stress response. Therefore, pharmacologic Nrf2 activation is a promising strategy for skin protection and cancer prevention. This study found that genetic Nrf2 activation in keratinocytes accelerates wound repair. Enhanced proliferation of cells of the pilosebaceous unit peripheral to the wound and a concomitant acceleration of re-epithelialization were identified as the underlying mechanism. Nrf2 specifically promoted the expansion of pilosebaceous cells expressing markers of junctional zone and upper isthmus follicular stem cells. This may result, at least in part, from the up-regulation of the direct Nrf2 target epigen and a concomitant increase in epidermal growth factor receptor signaling. The increase in pilosebaceous cells provided a larger pool of keratinocytes that migrate into the wound, resulting in faster wound closure. These results unravel a novel function of Nrf2 in wound repair and suggest the use of NRF2-activating compounds in patients with impaired healing.
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http://dx.doi.org/10.1016/j.ajpath.2018.11.017DOI Listing
March 2019

Evaluation of the Combination of Strip Gingival Grafts and a Xenogeneic Collagen Matrix for the Treatment of Severe Mucogingival Defects: A Human Histologic Study.

Int J Periodontics Restorative Dent 2019 Jan/Feb;39(1):9-14

Predictable and effective surgical techniques that aim to increase the width of keratinized gingiva, relocate the mucogingival junction, and deepen the vestibule often involve soft tissue autografts; however, soft tissue autograft supply is limited and its harvesting is associated with patient morbidity. With a strip autograft and xenogeneic collagen matrix (XCM) technique combination, autograft harvest requirements and patient morbidity are reduced. In this histologic evaluation, 12 strip autograft/XCM biopsy samples were compared with 3 reference samples of palatal strip autografts. Tissue morphology, keratin, and collagen expression appear identical, indicating that the combined grafting technique provides desired and physiologically normal keratinized gingiva.
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http://dx.doi.org/10.11607/prd.3921DOI Listing
April 2019

MicroRNA therapy for infected wounds.

EMBO Mol Med 2018 10;10(10)

Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute for Technology (ETH) Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.15252/emmm.201809574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180288PMC
October 2018

Olfactory dysfunction revisited: a reappraisal of work-related olfactory dysfunction caused by chemicals.

J Occup Med Toxicol 2018 4;13:28. Epub 2018 Sep 4.

Institute for Occupational Safety and Health of the German Social Accident Insurance, Unit Toxicology of Industrial Chemicals, Alte Heerstrasse 111, 53757 Sankt Augustin, Germany.

Occupational exposure to numerous individual chemicals has been associated with olfactory dysfunction, mainly in individual case descriptions. Comprehensive epidemiological investigations into the olfactotoxic effect of working substances show that the human sense of smell may be impaired by exposure to metal compounds involving cadmium, chromium and nickel, and to formaldehyde. This conclusion is supported by the results of animal experiments. The level of evidence for a relationship between olfactory dysfunction and workplace exposure to other substances is relatively weak.
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http://dx.doi.org/10.1186/s12995-018-0209-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124006PMC
September 2018

Nrf2-Mediated Fibroblast Reprogramming Drives Cellular Senescence by Targeting the Matrisome.

Dev Cell 2018 07;46(2):145-161.e10

Institute of Molecular Health Sciences, Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, Otto-Stern-Weg 7, 8093 Zurich, Switzerland. Electronic address:

Nrf2 is a key regulator of the antioxidant defense system, and pharmacological Nrf2 activation is a promising strategy for cancer prevention and promotion of tissue repair. Here we show, however, that activation of Nrf2 in fibroblasts induces cellular senescence. Using a combination of transcriptomics, matrix proteomics, chromatin immunoprecipitation and bioinformatics we demonstrate that fibroblasts with activated Nrf2 deposit a senescence-promoting matrix, with plasminogen activator inhibitor-1 being a key inducer of the senescence program. In vivo, activation of Nrf2 in fibroblasts promoted re-epithelialization of skin wounds, but also skin tumorigenesis. The pro-tumorigenic activity is of general relevance, since Nrf2 activation in skin fibroblasts induced the expression of genes characteristic for cancer-associated fibroblasts from different mouse and human tumors. Therefore, activated Nrf2 qualifies as a marker of the cancer-associated fibroblast phenotype. These data highlight the bright and the dark sides of Nrf2 and the need for time-controlled activation of this transcription factor.
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http://dx.doi.org/10.1016/j.devcel.2018.06.012DOI Listing
July 2018
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