TY  - JOUR
A1  - Däullary, Thomas
A1  - Imdahl, Fabian
A1  - Dietrich, Oliver
A1  - Hepp, Laura
A1  - Krammer, Tobias
A1  - Fey, Christina
A1  - Neuhaus, Winfried
A1  - Metzger, Marco
A1  - Vogel, Jörg
A1  - Westermann, Alexander J.
A1  - Saliba, Antoine-Emmanuel
A1  - Zdzieblo, Daniela
T1  - A primary cell-based in vitro model of the human small intestine reveals host olfactomedin 4 induction in response to Salmonella Typhimurium infection
JF  - Gut Microbes
N2  - Infection research largely relies on classical cell culture or mouse models. Despite having delivered invaluable insights into host-pathogen interactions, both have limitations in translating mechanistic principles to human pathologies. Alternatives can be derived from modern Tissue Engineering approaches, allowing the reconstruction of functional tissue models in vitro. Here, we combined a biological extracellular matrix with primary tissue-derived enteroids to establish an in vitro model of the human small intestinal epithelium exhibiting in vivo-like characteristics. Using the foodborne pathogen Salmonella enterica serovar Typhimurium, we demonstrated the applicability of our model to enteric infection research in the human context. Infection assays coupled to spatio-temporal readouts recapitulated the established key steps of epithelial infection by this pathogen in our model. Besides, we detected the upregulation of olfactomedin 4 in infected cells, a hitherto unrecognized aspect of the host response to Salmonella infection. Together, this primary human small intestinal tissue model fills the gap between simplistic cell culture and animal models of infection, and shall prove valuable in uncovering human-specific features of host-pathogen interplay.
KW  - intestinal enteroids
KW  - biological scaffold
KW  - Salmonella Typhimurium
KW  - OLFM4
KW  - NOTCH
KW  - filamentous Salmonella Typhimurium
KW  - bacterial migration
KW  - bacterial virulence
KW  - 3D tissue model
KW  - olfactomedin 4
KW  - infection
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350451
VL  - 15
IS  - 1
ER  - 
TY  - JOUR
A1  - Koenig, Leopold
A1  - Ramme, Anja Patricia
A1  - Faust, Daniel
A1  - Mayer, Manuela
A1  - Flötke, Tobias
A1  - Gerhartl, Anna
A1  - Brachner, Andreas
A1  - Neuhaus, Winfried
A1  - Appelt-Menzel, Antje
A1  - Metzger, Marco
A1  - Marx, Uwe
A1  - Dehne, Eva-Maria
T1  - A human stem cell-derived brain-liver chip for assessing blood-brain-barrier permeation of pharmaceutical drugs
JF  - Cells
N2  - Significant advancements in the field of preclinical in vitro blood-brain barrier (BBB) models have been achieved in recent years, by developing monolayer-based culture systems towards complex multi-cellular assays. The coupling of those models with other relevant organoid systems to integrate the investigation of blood-brain barrier permeation in the larger picture of drug distribution and metabolization is still missing. Here, we report for the first time the combination of a human induced pluripotent stem cell (hiPSC)-derived blood-brain barrier model with a cortical brain and a liver spheroid model from the same donor in a closed microfluidic system (MPS). The two model compounds atenolol and propranolol were used to measure permeation at the blood–brain barrier and to assess metabolization. Both substances showed an in vivo-like permeation behavior and were metabolized in vitro. Therefore, the novel multi-organ system enabled not only the measurement of parent compound concentrations but also of metabolite distribution at the blood-brain barrier.
KW  - blood-brain barrier (BBB) model
KW  - human induced pluripotent stem cells (hiPSCs)
KW  - microphysiological systems (MPS)
KW  - multi-organ chip
KW  - brain–liver chip
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290375
SN  - 2073-4409
VL  - 11
IS  - 20
ER  - 
TY  - JOUR
A1  - Appelt-Menzel, Antje
A1  - Cubukova, Alevtina
A1  - Günther, Katharina
A1  - Edenhofer, Frank
A1  - Piontek, Jörg
A1  - Krause, Gerd
A1  - Stüber, Tanja
A1  - Walles, Heike
A1  - Neuhaus, Winfried
A1  - Metzger, Marco
T1  - Establishment of a Human Blood-Brain Barrier Co-culture Model Mimicking the Neurovascular Unit Using Induced Pluri- and Multipotent Stem Cells
JF  - Stem Cell Reports
N2  - In vitro models of the human blood-brain barrier (BBB) are highly desirable for drug development. This study aims to analyze a set of ten different BBB culture models based on primary cells, human induced pluripotent stem cells (hiPSCs), and multipotent fetal neural stem cells (fNSCs). We systematically investigated the impact of astrocytes, pericytes, and NSCs on hiPSC-derived BBB endothelial cell function and gene expression. The quadruple culture models, based on these four cell types, achieved BBB characteristics including transendothelial electrical resistance (TEER) up to 2,500 Ω cm\(^{2}\) and distinct upregulation of typical BBB genes. A complex in vivo-like tight junction (TJ) network was detected by freeze-fracture and transmission electron microscopy. Treatment with claudin-specific TJ modulators caused TEER decrease, confirming the relevant role of claudin subtypes for paracellular tightness. Drug permeability tests with reference substances were performed and confirmed the suitability of the models for drug transport studies.
KW  - blood-brain barrier (BBB) model
KW  - human induced pluripotent stem cells (hiPSCs)human induced pluripotent stem cells (hiPSCs)
KW  - multipotent fetal neural stem cells (fNSCs)
KW  - neurovascular unit in vitro
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170982
VL  - 8
IS  - 4
ER  -