Suter-Dick, Laura
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Laura
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Suter-Dick, Laura
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- 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
- PublikationThe role of bile salts in cholestatic injury and fibrosis using a human 3D in vitro model(11/2018) Messner, Catherine; Mauch, Linda; Mannino, Salvatore; Prestigiacomo, Vincenzo; Suter-Dick, Laura06 - Präsentation
- Publikation3D human liver microtissues vs. 2D monolayer culture as an in vitro tool for compound testing(10/2018) Messner, Catherine; Prestigiacomo, Vincenzo; Mannino, Salvatore; Mauch, Linda; Suter-Dick, Laura06 - Präsentation
- 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
- PublikationHuman 3D-cocultures for the study of toxicant induced liver fibrosis(2016) Suter-Dick, Laura; Prestigiacomo, Vincenzo; Lampart, Franziska06 - Präsentation
- PublikationHuman 3D-model for the investigation of hepatic fib rosis(2015) Suter-Dick, Laura; Prestigiacomo, Vincenzo06 - Präsentation