Suter-Dick, Laura

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Suter-Dick
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Laura
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Suter-Dick, Laura

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2020 - 202213
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Enddatum: 2022 × Anfangsdatum: 2020 ×

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  • Vorschaubild
    Publikation
    Methotrexate-induced liver injury is associated with oxidative stress, impaired mitochondrial respiration, and endoplasmic reticulum stress in vitro
    (MDPI, 01.12.2022) Schmidt, Saskia; Messner, Catherine; Gaiser, Carine; Hämmerli, Carina; Suter-Dick, Laura [in: International Journal of Molecular Sciences]
    Low-dose methotrexate (MTX) is a standard therapy for rheumatoid arthritis due to its low cost and efficacy. Despite these benefits, MTX has been reported to cause chronic drug-induced liver injury, namely liver fibrosis. The hallmark of liver fibrosis is excessive scarring of liver tissue, triggered by hepatocellular injury and subsequent activation of hepatic stellate cells (HSCs). However, little is known about the precise mechanisms through which MTX causes hepatocellular damage and activates HSCs. Here, we investigated the mechanisms leading to hepatocyte injury in HepaRG and used immortalized stellate cells (hTERT-HSC) to elucidate the mechanisms leading to HSC activation by exposing mono- and co-cultures of HepaRG and hTERT-HSC to MTX. The results showed that at least two mechanisms are involved in MTX-induced toxicity in HepaRG: (i) oxidative stress through depletion of glutathione (GSH) and (ii) impairment of cellular respiration in a GSH-independent manner. Furthermore, we measured increased levels of endoplasmic reticulum (ER) stress in activated HSC following MTX treatment. In conclusion, we established a human-relevant in vitro model to gain mechanistical insights into MTX-induced hepatotoxicity, linked oxidative stress in HepaRG to a GSH-dependent and -independent pathway, and hypothesize that not only oxidative stress in hepatocytes but also ER stress in HSCs contribute to MTX-induced activation of HSCs.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    Apical medium flowiInfluences the morphology and physiology of human proximal tubular cells in a microphysiological system
    (MDPI, 30.09.2022) Specioso, Gabriele; Bovard, David; Zanetti, Filippo; Maranzano, Fabio; Merg, Céline; Sandoz, Antonin; Titz, Bjoern; Dalcanale, Federico; Hoeng, Julia; Renggli, Kasper; Suter-Dick, Laura [in: Bioengineering]
    There is a lack of physiologically relevant in vitro human kidney models for disease modelling and detecting drug-induced effects given the limited choice of cells and difficulty implementing quasi-physiological culture conditions. We investigated the influence of fluid shear stress on primary human renal proximal tubule epithelial cells (RPTECs) cultured in the micro-physiological Vitrofluid device. This system houses cells seeded on semipermeable membranes and can be connected to a regulable pump that enables controlled, unidirectional flow. After 7 days in culture, RPTECs maintained physiological characteristics such as barrier integrity, protein uptake ability, and expression of specific transporters (e.g., aquaporin-1). Exposure to constant apical side flow did not cause cytotoxicity, cell detachment, or intracellular reactive oxygen species accumulation. However, unidirectional flow profoundly affected cell morphology and led to primary cilia lengthening and alignment in the flow direction. The dynamic conditions also reduced cell proliferation, altered plasma membrane leakiness, increased cytokine secretion, and repressed histone deacetylase 6 and kidney injury molecule 1 expression. Cells under flow also remained susceptible to colistin-induced toxicity. Collectively, the results suggest that dynamic culture conditions in the Vitrofluid system promote a more differentiated phenotype in primary human RPTECs and represent an improved in vitro kidney model.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    Directional submicrofiber hydrogel composite scaffolds supporting neuron differentiation and enabling neurite alignment
    (MDPI, 29.09.2022) Selvi, Jasmin; Faia-Torres, Ana Bela; Rühe, Jürgen; Züger, Fabian; Suter-Dick, Laura; Mungenast, Lena; Gullo, Maurizio [in: International Journal of Molecular Sciences]
    Cell cultures aiming at tissue regeneration benefit from scaffolds with physiologically relevant elastic moduli to optimally trigger cell attachment, proliferation and promote differentiation, guidance and tissue maturation. Complex scaffolds designed with guiding cues can mimic the anisotropic nature of neural tissues, such as spinal cord or brain, and recall the ability of human neural progenitor cells to differentiate and align. This work introduces a cost-efficient gelatin-based submicron patterned hydrogel–fiber composite with tuned stiffness, able to support cell attachment, differentiation and alignment of neurons derived from human progenitor cells. The enzymatically crosslinked gelatin-based hydrogels were generated with stiffnesses from 8 to 80 kPa, onto which poly(ε-caprolactone) (PCL) alignment cues were electrospun such that the fibers had a preferential alignment. The fiber–hydrogel composites with a modulus of about 20 kPa showed the strongest cell attachment and highest cell proliferation, rendering them an ideal differentiation support. Differentiated neurons aligned and bundled their neurites along the aligned PCL filaments, which is unique to this cell type on a fiber–hydrogel composite. This novel scaffold relies on robust and inexpensive technology and is suitable for neural tissue engineering where directional neuron alignment is required, such as in the spinal cord.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    3D printed microfluidic modules. Passive mixers and cells encapsulation in alginate
    (De Gruyter, 02.09.2022) Dalcanale, Federico; Caj, Michaela; Schuler, Felix; Ganeshanathan, Kireedan; Suter-Dick, Laura [in: Current Directions in Biomedical Engineering]
    Passive mixers and droplet generation microfluidic chip modules were designed and manufactured using a commercial SLA 3D-printer. The mixing modules were designed specifically for 3D-printing and evaluated using FEM modeling. The co-flow droplet generator was used for cancer cells encapsulation and drug potency evaluation.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild nicht verfügbar
    Publikation
    How 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
  • Vorschaubild nicht verfügbar
    Publikation
    Evaluation 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
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    Publikation
    Single Cell Gene Expression analysis in a 3D microtissue liver model reveals cell type-specific responses to pro-fibrotic TGF-β1 stimulation
    (MDPI, 22.04.2021) Messner, Catherine; Babrak, Lmar; Titolo, Gaia; Caj, Michaela; Miho, Enkelejda; Suter-Dick, Laura [in: International Journal of Molecular Sciences]
    3D cell culture systems are widely used to study disease mechanisms and therapeutic interventions. Multicellular liver microtissues (MTs) comprising HepaRG, hTERT-HSC and THP-1 maintain multicellular interactions and physiological properties required to mimic liver fibrosis. However, the inherent complexity of multicellular 3D-systems often hinders the discrimination of cell type specific responses. Here, we aimed at applying single cell sequencing (scRNA-seq) to discern the molecular responses of cells involved in the development of fibrosis elicited by TGF-β1. To obtain single cell suspensions from the MTs, an enzymatic dissociation method was optimized. Isolated cells showed good viability, could be re-plated and cultured in 2D, and expressed specific markers determined by scRNA-seq, qRT-PCR, ELISA and immunostaining. The three cell populations were successfully clustered using supervised and unsupervised methods based on scRNA-seq data. TGF-β1 led to a fibrotic phenotype in the MTs, detected as decreased albumin and increased αSMA expression. Cell-type specific responses to the treatment were identified for each of the three cell types. They included HepaRG damage characterized by a decrease in cellular metabolism, prototypical inflammatory responses in THP-1s and extracellular matrix remodeling in hTERT-HSCs. Furthermore, we identified novel cell-specific putative fibrosis markers in hTERT-HSC (COL15A1), and THP-1 (ALOX5AP and LAPTM5).
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    Implementation of a human renal proximal tubule on a chip for nephrotoxicity and drug interaction studies
    (Elsevier, 04.04.2021) Suter-Dick, Laura; Caj, Michaela; Hutter, Simon; Vormann, Marianne; Vriend, Jelle; Lanz, Henriette; Gijzen, Linda; van den Heuvel, Angelique; Joore, Jos; Trietsch, Sebastian; Stuut, Christaan; Nieskens, Tom T.G.; Peters, Janny; Ramp, Daniela; Russel, Frans; Roth, Adrian; Lu, Shuyan; Polli, Joseph; Jacobsen, Björn [in: Journal of Pharmaceutical Sciences]
    Proximal tubule epithelial cells (PTEC) are susceptible to drug-induced kidney injury (DIKI). Cell-based, two-dimensional (2D) in vitro PTEC models are often poor predictors of DIKI, probably due to the lack of physiological architecture and flow. Here, we assessed a high throughput, 3D microfluidic platform (Nephroscreen) for the detection of DIKI in pharmaceutical development. This system was established with four model nephrotoxic drugs (cisplatin, tenofovir, tobramycin and cyclosporin A) and tested with eight pharmaceutical compounds. Measured parameters included cell viability, release of lactate dehydrogenase (LDH) and N-acetyl-β-d-glucosaminidase (NAG), barrier integrity, release of specific miRNAs, and gene expression of toxicity markers. Drug-transporter interactions for P-gp and MRP2/4 were also determined. The most predictive read outs for DIKI were a combination of cell viability, LDH and miRNA release. In conclusion, Nephroscreen detected DIKI in a robust manner, is compatible with automated pipetting, proved to be amenable to long-term experiments, and was easily transferred between laboratories. This proof-of-concept-study demonstrated the usability and reproducibility of Nephroscreen for the detection of DIKI and drug-transporter interactions. Nephroscreen it represents a valuable tool towards replacing animal testing and supporting the 3Rs (Reduce, Refine and Replace animal experimentation).
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    Nephroscreen. A robust and versatile renal tubule-on-a-chip platform for nephrotoxicity assessment
    (Elsevier, 03/2021) Suter-Dick, Laura; Vriend, Jelle; Vormann, Marianne; Lanz, Henriette; Joore, Jos; Trietsch, Sebastian J.; Russel, Frans; Jacobsen, Björn; Roth, Adrian; Lu, Shuyan; Polli, Joseph; Naidoo, Anita; Masereeuw, Rosalinde; Wilmer, Martijn [in: Current Opinion in Toxicology]
    Proximal tubule epithelial cells are the main driver of renal transport and secretion of xenobiotics, making them susceptible to drug-induced kidney injury. Cell-based assays are a meaningful alternative to animal testing to detect nephrotoxicity and contribute to the 3Rs (refine, reduce, replace animal experimentation). Here we report on a high-throughput, three-dimensional microfluidic platform (Nephroscreen) to detect drug-induced nephrotoxicity. Toxicologically relevant parameters were used to assess cell viability, functional epithelial barrier integrity, and interactions with specific transporters (P-glycoprotein: P-gp and multidrug resistance–associated protein 2/4: MRP2/4). Nephroscreen allowed the combination of a variety of read-outs, including imaging, extracellularly released markers, intracellular markers, and functional assays. Nephroscreen is compatible with automated pipetting, proved to be amenable to long-term experiments (at least 11 days), and was easily transferred between laboratories. The compelling data originate from several published reports on the development and implementation of this platform to detect nephrotoxicity and drug–transporter interactions. The reports demonstrate that Nephroscreen could be used to detect the nephrotoxic liabilities of the tested compounds. Future directions should include additional test compounds and thorough validation of its performance.
    01A - Beitrag in wissenschaftlicher Zeitschrift
  • Vorschaubild
    Publikation
    Identification of miR-199a-5p, miR-214-3p and miR-99b-5p as fibrosis-specific extracellular biomarkers and promoters of HSC activation
    (MDPI, 2021) Suter-Dick, Laura; Messner, Catherine; Özkul, Dilek; Gaiser, Carine; Schmidt, Saskia; Terraciano, Luigi; Krähenbühl, Stephan [in: International Journal of Molecular Sciences]
    Liver fibrosis is characterized by the accumulation of extracellular matrix (ECM) resulting in the formation of fibrous scars. In the clinic, liver biopsies are the standard diagnostic method despite the potential for clinical complications. miRNAs are single-stranded, non-coding RNAs that can be detected in tissues, body fluids and cultured cells. The regulation of many miRNAs has been linked to tissue damage, including liver fibrosis in patients, resulting in aberrant miRNA expression/release. Experimental evidence also suggests that miRNAs are regulated in a similar manner in vitro and could thus serve as translational in vitro–in vivo biomarkers. In this work, we set out to identify and characterize biomarkers for liver fibrosis that could be used in vitro and clinically for research and diagnostic purposes. We focused on miRNAs released from hepatic 3D cultures exposed to methotrexate (MTX), which causes fibrosis, and acetaminophen (APAP), an acute hepatotoxicant with no clinically relevant association to liver fibrosis. Using a 3D in vitro model, we corroborated compound-specific responses as we show MTX induced a fibrotic response, and APAP did not. Performing miRNA-seq of cell culture supernatants, we identified potential miRNA biomarkers (miR-199a-5p, miR-214-3p, niRNA-125a-5p and miR-99b-5p) that were associated with a fibrotic phenotype and not with hepatocellular damage alone. Moreover, transfection of HSC with miR-199a-5p led to decreased expression of caveolin-1 and increased α-SMA expression, suggesting its role in HSC activation. In conclusion, we propose that extracellular miR-214-3p, miR-99b-5p, miR-125a-5p and specifically miR-199a-5p could contribute towards a panel of miRNAs for identifying liver fibrosis and that miR-199a-5p, miR-214-3p and miR-99b-5p are promoters of HSC activation.
    01A - Beitrag in wissenschaftlicher Zeitschrift