Suter-Dick, Laura
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Suter-Dick, Laura
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- PublikationEnvironmentally relevant UV-light weathering of polystyrene micro- and nanoplastics promotes hepatotoxicity in a human cell line(Royal Society of Chemistry, 2023) Englert, Felix H.; Mueller, Fabrice A.; Dugershaw-Kurzer, Battuja; Kissling, Vera M.; Boentges, Sarah; Gupta, Govind S.; Fontana, Gabriele A.; Diedrich, Sabine; Suter-Dick, Laura; Sturla, Shana J.; Buerki-Thurnherr, Tina [in: Environmental Science: Nano]Environmentally-relevant concentrations of UV-weathered polystyrene micro and nanoplastics induce hepatotoxicity and considerable changes in gene expression of liver disease-relevant pathways.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationHow to Foster ‘New Approach Methodology’ Toxicologists(SAGE, 18.02.2022) Doktorova, Tatyana Y.; Azzi, Pamela; Hofer, Joelle; Werner, Sophie; Singh, Pranika; Hardy, Barry; Chesne, Christophe; Messner, Catherine; Gaiser, Carine; Suter-Dick, Laura [in: Alternatives to Laboratory Animals]The need to reduce, refine and replace animal experimentation has led to a boom in the establishment of new approach methodologies (NAMs). This promising trend brings the hope that the replacement of animals by using NAMs will become increasingly accepted by regulators, included in legislation, and consequently more-often implemented by industry. The majority of NAMs, however, are still not very well understood, either due to the complexity of the applied approach or the data analysis workflow. A potential solution to this problem is the provision of better educational resources to scientists new to the area — showcasing the added value of NAMs and outlining various ways of overcoming issues associated with knowledge gaps. In this paper, the educational exchange between four institutions — namely, two universities and two SMEs — via a series of video training sessions, is described. The goal of this exchange was to showcase an exemplary event to help introduce scientists to non-animal approaches, and to actively support the development of resources enabling the use of alternatives to laboratory animals.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationEvaluation of dioxin induced transcriptomic responses in a 3D human liver microtissue model(Elsevier, 2022) Tian, Mingming; Gou, Xiao; Zhang, Xiaowei; Messner, Catherine; Suter-Dick, Laura; Yan, Lu [in: Environmental Research]Three-dimensional human liver microtissue model provides a promising method for predicting the human hepatotoxicity of environmental chemicals. However, the dynamics of transcriptional responses of 3D human liver microtissue model to dioxins exposure remain unclear. Herein, time-series transcriptomic analysis was used to characterize modulation of gene expression over 14 days in 3D human liver microtissues exposed to 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD, 31 nM, 10 ng/ml). Changes in gene expression and modulation of biological pathways were evaluated at several time points. The results showed that microtissues stably expressed genes related to toxicological pathways (e.g. highly of genes involved in external stimuli and maintenance of cell homeostasis pathways) during the 14-day culture period. Furthermore, a weekly phenomenon pattern was observed for the number of the differentially expressed genes in microtissues exposed to TCDD at each time point. TCDD led to an induction of genes involved in cell cycle regulation at day three. Metabolic pathways were the main significantly induced pathways during the subsequent days, with the immune/inflammatory response enriched on the fifth day, and the cellular response to DNA damage was identified at the end of the exposure. Finally, relevant transcription patterns identified in microtissues were compared with published data on rodent and human cell-line studies to elucidate potential species-specific responses to TCDD over time. Cell development and cytochrome P450 pathway were mainly affected after a 3-day exposure, with the DNA damage response identified at the end of exposure in the human microtissue system but not in mouse/rat primary hepatocytes models. Overall, the 3D human liver microtissue model is a valuable tool to predict the toxic effects of environmental chemicals with a relatively long exposure.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationAssessment of fibrotic pathways induced by environmental chemicals using 3D-human liver microtissue model(Elsevier, 30.12.2020) Lu, Yan; Messner, Catherine; Suter-Dick, Laura [in: Environmental Research]Exposure to environmental chemicals, particularly those with persistent and bioaccumulative properties have been linked to liver diseases. Induction of fibrotic pathways is considered as a pre-requirement of chemical induced liver fibrosis. Here, we applied 3D in vitro human liver microtissues (MTs) composed of HepaRG, THP-1 and hTERT-HSC that express relevant hepatic pathways (bile acid, sterol, and xenobiotic metabolism) and can recapitulate key events of liver fibrosis (e.g. extracellular matrix-deposition). The liver MTs were exposed to a known profibrotic chemical, thioacetamide (TAA) and three representative environmental chemicals (TCDD, benzo [a] pyrene (BaP) and PCB126). Both TAA and BaP triggered fibrotic pathway related events such as he-patocellular damage (cytotoxicity and decreased albumin release), hepatic stellate cell activation (transcriptional upregulation of α-SMA and Col1α1) and extracellular matrix remodelling. TCDD or PCB126 at measured con-centrations did not elicit these responses in the 3D liver MTs system, though they caused cytotoxicity in HepaRG monoculture at high concentrations. Reduced human transcriptome (RHT) analysis captured molecular re-sponses involved in liver fibrosis when MTs were treated with TAA and BaP. The results suggest that 3D, multicellular, human liver microtissues represent an alternative, human-relevant, in vitro liver model for assessing fibrotic pathways induced by environmental chemicals.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationSwiss Startup Framework: A Highly Effective Network Supporting the Generation of Emerging Biotech Businesses(Schweizerische Chemische Gesellschaft, 28.10.2020) Suter-Dick, Laura; Mitchell, Isabelle [in: Chimia]For over 50 years, Switzerland has been one of the leading countries driving innovation in biotechnology and its industrial applications. Today, some 1,000 biotech companies form a tightly knit, cross-functional network ranging from research through to manufacturing. This network comprises R&D companies, contract research organizations, and highly specialized advisors and biotech investors. Together, they form an external innovation pool that complements the in-house R&D capacity of the large multi-national pharma companies. A highly effective startup framework, solid acceleration mechanisms, and innovative investors enable the emergence of a continuous flow of biotech startups that revitalize the industry with new technologies and products supporting drug development and diagnostics.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationExosomal microRNAs Release as a Sensitive Marker for Drug-Induced Liver Injury In Vitro(Mary Ann Liebert, 16.09.2020) Messner, Catherine; Premand, Carine; Gaiser, Carine; Kluser, Tanja; Kübler, Eric; Suter-Dick, Laura [in: Applied In Vitro Toxicology]01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationRat multicellular 3D liver microtissues to explore TGF-β1 induced effects(Elsevier, 13.11.2019) Prestigiacomo, Vincenzo; Weston, Anna; Suter-Dick, Laura [in: Journal of Pharmacological and Toxicological Methods]Chronic liver damage can lead to fibrosis, encompassing hepatocellular injury, activation of Kupffer cells (KC), and activation of hepatic stellate cells (HSC). Inflammation and TGF-β1 are known mediators in the liver fibrosis adverse outcome pathway (AOP). The aim of this project was to develop a suitable rodent cell culture model for the investigation of key events involved in the development of liver fibrosis, specifically the responses to pathophysiological stimuli such as TGF-β1 and LPS-triggered inflammation. We optimized a single step protocol to purify rat primary hepatocytes (Hep), HSC and KC cells to generate 3D co-cultures based on the hanging drop method. This primary multicellular model responded to the profibrotic cytokine TGF-β1 (1 ng/mL) with signs of hepatocellular damage, inflammation and ultimately HSC activation (increase in αSMA expression). LPS elicited an inflammatory response characterized by increased expression of cytokines. 3D-monocultures comprising only Hep displayed different responses, underlying that parenchymal and non-parenchymal cells need to be present in the system to recapitulate fibrosis. The data also suggest that pre-activated HSC may reverse to a quiescent phenotype in 3D, probably due to the more physiological conditions.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationNephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules(08/2018) Vormann, Marianne K.; Gijzen, Linda; Hutter, Simon; Boot, Lisette; Nicolas, Arnaud; van den Heuvel, Angelique; Vriend, Jelle; Ng, Chee Ping; Nieskens, Tom T.G.; van Duinen, Vincent; de Wagenaar, Bjorn; Masereeuw, Rosalinde; Suter-Dick, Laura; Trietsch, Sebastian J.; Wilmer, Martijn; Joore, Jos; Vulto, Paul; Lanz, Henriette [in: The AAPS Journal]Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationNrf2 protects stellate cells from Smad-dependent cell activation(Public Library of Science, 07/2018) Prestigiacomo, Vincenzo; Suter-Dick, Laura [in: PLOS ONE]Hepatic stellate cells (HSC) orchestrate the deposition of extracellular matrix (ECM) and are the primary effector of liver fibrosis. Several factors, including TGF-β1, PDGF and oxidative stress, have been shown to trigger HSC activation. However, the involvement of cellular defence mechanisms, such as the activation of antioxidant response by Nrf2/Keap1 in the modulation of HSC activation is not known. The aim of this work was to elucidate the role of Nrf2 pathway in HSC trans-differentiation involved in the development of fibrosis. To this end, we repressed Nrf2 and Keap1 expression in HSC with specific siRNAs. We then assessed activation markers, as well as proliferation and migration, in both primary and immortalised human HSCs exposed to Smad inhibitors (SB-431542 hydrate and SB-525334), TGF-β1 and/or PDGF. Our results indicate that knocking down Nrf2 induces HSC activation, as shown by an increase in αSMA-positive cells and by gene expression induction of ECM components (collagens and fibronectin). HSC with reduced Nrf2-levels also showed an increase in migration and a decrease in proliferation. We could also demonstrate that the activation of Nrf2-deficient HSC involves the TGF-β1/Smad pathway, as the activation was successfully inhibited with the two tested Smad inhibitors. Moreover, TGF-β1 elicited a stronger induction of HSC activation markers in Nrf2 deficient cells than in wild type cells. Thus, our data suggest that Nrf2 limits HSCs activation, through the inhibition of the TGF-β1/Smad pathway in HSCs.01A - Beitrag in wissenschaftlicher Zeitschrift
- PublikationCombining Extracellular miRNA Determination with Microfluidic 3D Cell Cultures for the Assessment of Nephrotoxicity: a Proof of Concept Study(07/2018) Suter-Dick, Laura; Mauch, Linda; Ramp, Daniela; Caj, Michaela; Vormann, Marianne K.; Hutter, Simon; Lanz, Henriette; Vriend, Jelle; Masereeuw, Rosalinde; Wilmer, Martijn [in: The AAPS Journal]Drug-induced kidney injury is often observed in the clinics and can lead to long-term organ failure. In this work, we evaluated a novel in vitro system that aims at detecting whether compounds can cause renal proximal tubule damage in man. For this, we implemented organotypic cultures of human conditionally immortalized proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1) in a three-channel OrganoPlate under microfluidic conditions. Cells were exposed to four known nephrotoxicants (cisplatin, tenofovir, cyclosporine A, and tobramycin). The effect on cell viability and NAG release into the medium was determined. A novel panel of four miRNAs (mir-21, mir-29a, mir-34a, and mir-192) was selected as potential biomarkers of proximal tubule damage. After nephrotoxicant treatment, miRNA levels in culture medium were earlier indicators than cell viability (WST-8 assay) and outperformed NAG for proximal tubule damage. In particular, mir-29a, mir-34a, and mir-192 were highly reproducible between experiments and across compounds, whereas mir-21 showed more variability. Moreover, similar data were obtained in two different laboratories, underlining the reproducibility and technical transferability of the results, a key requirement for the implementation of novel biomarkers. In conclusion, the selected miRNAs behaved like sensitive biomarkers of damage to tubular epithelial cells caused by several nephrotoxicity mechanisms. This biomarker panel, in combination with the 3D cultures of ciPTEC-OAT1 in the OrganoPlate, represents a novel tool for in vitro nephrotoxicity detection. These results pave the way for the application of miRNAs in longitudinal, time-course in vitro toxicity studies.01A - Beitrag in wissenschaftlicher Zeitschrift