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A perfused in vitro human iPSC-derived blood–brain barrier faithfully mimics transferrin receptor-mediated transcytosis of therapeutic antibodies
(Springer, 2023) Burgio, Floriana; Gaiser, Carine; Brady, Kevin; Gatta, Viviana; Class, Reiner; Schrage, Ramona; Suter-Dick, Laura
Delivering biologics to elicit a therapeutic response in the central nervous system (CNS) remains challenging due to the presence of the blood brain barrier (BBB). Receptor-mediated transcytosis is a strategy to improve brain exposure after systemic drug administration. The availability of a clinically relevant in vitro BBB model is crucial to investigate transcytosis pathways and to predict the penetration of biologics into the CNS. We created a perfused human in vitro BBB model made of induced pluripotent stem cells (iPSC)-derived brain microvascular endothelial cells (BMEC) for studying transferrin receptor-mediated transcytosis. iPSC-derived BMEC were seeded in the top channel of a three-lane microfluidic device (OrganoPlate®). After 2 days in culture, the established cell model exhibited relevant BBB features, including physiological transendothelial electrical resistance in a transwell setting (1500 Ω*cm), reduced apparent permeability (Papp) to the fluorescence tracer Lucifer yellow (20-fold less than cell-free chips), expression of key BBB markers such as tight junctions proteins, transporters, receptors and functional P-gp efflux pump. Moreover, the model exhibited functional transferrin receptor-mediated uptake and transcytosis. To assess selective transferrin receptor-mediated transcytosis, a mixture of anti-human transferrin receptor (MEM-189) and control (sheep IgG anti-bovine serum albumin) antibodies was perfused in the top channel for 2 h. The Papp of MEM-189 was 11-fold higher than that of the control antibody, demonstrating facilitated receptor-mediated transcytosis. Compared to published work reporting a 2-fold ratio, this result is remarkable and establishes the suitability of our model for exploring receptor-mediated transcytosis and screening of antibodies for putative brain shuttle application. A perfused in vitro human model made of iPSC-derived BMEC with the chief characteristics (barrier tightness, functionality) of the human BBB can be applied to study transferrin receptor (TfR)-mediated transcytosis of therapeutic antibodies. This may bring critical advances in drug shuttle technology. Graphical abstract generated with biorender.com.
01A - Beitrag in wissenschaftlicher Zeitschrift
Electrospun decellularized extracellular matrix scaffolds promote the regeneration of injured neurons
(Elsevier, 09/2023) Mungenast, Lena; Nieminen, Ronya; Gaiser, Carine; Faia-Torres, Ana Bela; Rühe, Jürgen; Suter-Dick, Laura
01A - Beitrag in wissenschaftlicher Zeitschrift
Environmentally 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
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
In vitro to in vivo extrapolation and high-content imaging for simultaneous characterization of chemically induced liver steatosis and markers of hepatotoxicity
(Springer, 12.04.2023) Müller, Fabrice A.; Stamou, Marianna; Englert, Felix H.; Frenzel, Ole; Diedrich, Sabine; Suter-Dick, Laura; Wambaugh, John F.; Sturla, Shana J.
Chemically induced steatosis is characterized by lipid accumulation associated with mitochondrial dysfunction, oxidative stress and nucleus distortion. New approach methods integrating in vitro and in silico models are needed to identify chemicals that may induce these cellular events as potential risk factors for steatosis and associated hepatotoxicity. In this study we used high-content imaging for the simultaneous quantification of four cellular markers as sentinels for hepatotoxicity and steatosis in chemically exposed human liver cells in vitro. Furthermore, we evaluated the results with a computational model for the extrapolation of human oral equivalent doses (OED). First, we tested 16 reference chemicals with known capacities to induce cellular alterations in nuclear morphology, lipid accumulation, mitochondrial membrane potential and oxidative stress. Then, using physiologically based pharmacokinetic modeling and reverse dosimetry, OEDs were extrapolated from data of any stimulated individual sentinel response. The extrapolated OEDs were confirmed to be within biologically relevant exposure ranges for the reference chemicals. Next, we tested 14 chemicals found in food, selected from thousands of putative chemicals on the basis of structure-based prediction for nuclear receptor activation. Amongst these, orotic acid had an extrapolated OED overlapping with realistic exposure ranges. Thus, we were able to characterize known steatosis-inducing chemicals as well as data-scarce food-related chemicals, amongst which we confirmed orotic acid to induce hepatotoxicity. This strategy addresses needs of next generation risk assessment and can be used as a first chemical prioritization hazard screening step in a tiered approach to identify chemical risk factors for steatosis and hepatotoxicity-associated events.
01A - Beitrag in wissenschaftlicher Zeitschrift

Institut für Chemie und Bioanalytik

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