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

Environmentally-relevant concentrations of UV-weathered polystyrene micro and nanoplastics induce hepatotoxicity and considerable changes in gene expression of liver disease-relevant pathways.

2020-12-30, Lu, Yan, Messner, Catherine, Suter-Dick, Laura

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.

2019-11-13, Prestigiacomo, Vincenzo, Weston, Anna, Suter-Dick, Laura

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.

2018-11, Messner, Catherine, Mauch, Linda, Mannino, Salvatore, Prestigiacomo, Vincenzo, Suter-Dick, Laura

2022-02-18, Doktorova, Tatyana Y., Azzi, Pamela, Hofer, Joelle, Werner, Sophie, Singh, Pranika, Hardy, Barry, Chesne, Christophe, Messner, Catherine, Gaiser, Carine, Suter-Dick, Laura

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.

2020-10-28, Suter-Dick, Laura, Mitchell, Isabelle

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.

2019, Suter-Dick, Laura, Greim, Helmut, Snyder, Robert

2022, Tian, Mingming, Gou, Xiao, Zhang, Xiaowei, Messner, Catherine, Suter-Dick, Laura, Yan, Lu

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.

2020-09-16, Messner, Catherine, Premand, Carine, Gaiser, Carine, Kluser, Tanja, Kübler, Eric, Suter-Dick, Laura

2018-11, Suter-Dick, Laura