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  - 
TY  - JOUR
A1  - Herbert, Saskia-Laureen
A1  - Fick, Andrea
A1  - Heydarian, Motaharehsadat
A1  - Metzger, Marco
A1  - Wöckel, Achim
A1  - Rudel, Thomas
A1  - Kozjak-Pavlovic, Vera
A1  - Wulff, Christine
T1  - Establishment of the SIS scaffold-based 3D model of human peritoneum for studying the dissemination of ovarian cancer
JF  - Journal of Tissue Engineering
N2  - Ovarian cancer is the second most common gynecological malignancy in women. More than 70% of the cases are diagnosed at the advanced stage, presenting as primary peritoneal metastasis, which results in a poor 5-year survival rate of around 40%. Mechanisms of peritoneal metastasis, including adhesion, migration, and invasion, are still not completely understood and therapeutic options are extremely limited. Therefore, there is a strong requirement for a 3D model mimicking the in vivo situation. In this study, we describe the establishment of a 3D tissue model of the human peritoneum based on decellularized porcine small intestinal submucosa (SIS) scaffold. The SIS scaffold was populated with human dermal fibroblasts, with LP-9 cells on the apical side representing the peritoneal mesothelium, while HUVEC cells on the basal side of the scaffold served to mimic the endothelial cell layer. Functional analyses of the transepithelial electrical resistance (TEER) and the FITC-dextran assay indicated the high barrier integrity of our model. The histological, immunohistochemical, and ultrastructural analyses showed the main characteristics of the site of adhesion. Initial experiments using the SKOV-3 cell line as representative for ovarian carcinoma demonstrated the usefulness of our models for studying tumor cell adhesion, as well as the effect of tumor cells on endothelial cell-to-cell contacts. Taken together, our data show that the novel peritoneal 3D tissue model is a promising tool for studying the peritoneal dissemination of ovarian cancer.
KW  - ovarian cancer
KW  - 3D tissue model
KW  - co-culture
KW  - peritoneal metastasis
KW  - cancer dissemination
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301311
SN  - 2041-7314
VL  - 13
ER  - 
TY  - JOUR
A1  - Kühnemundt, Johanna
A1  - Leifeld, Heidi
A1  - Scherg, Florian
A1  - Schmitt, Matthias
A1  - Nelke, Lena C.
A1  - Schmitt, Tina
A1  - Bauer, Florentin
A1  - Göttlich, Claudia
A1  - Fuchs, Maximilian
A1  - Kunz, Meik
A1  - Peindl, Matthias
A1  - Brähler, Caroline
A1  - Kronenthaler, Corinna
A1  - Wischhusen, Jörg
A1  - Prelog, Martina
A1  - Walles, Heike
A1  - Dandekar, Thomas
A1  - Dandekar, Gudrun
A1  - Nietzer, Sarah L.
T1  - Modular micro-physiological human tumor/tissue models based on decellularized tissue for improved preclinical testing
JF  - ALTEX
N2  - High attrition-rates entailed by drug testing in 2D cell culture and animal models stress the need for improved modeling of human tumor tissues. In previous studies our 3D models on a decellularized tissue matrix have shown better predictivity and higher chemoresistance. A single porcine intestine yields material for 150 3D models of breast, lung, colorectal cancer (CRC) or leukemia. The uniquely preserved structure of the basement membrane enables physiological anchorage of endothelial cells and epithelial-derived carcinoma cells. The matrix provides different niches for cell growth: on top as monolayer, in crypts as aggregates and within deeper layers. Dynamic culture in bioreactors enhances cell growth. Comparing gene expression between 2D and 3D cultures, we observed changes related to proliferation, apoptosis and stemness. For drug target predictions, we utilize tumor-specific sequencing data in our in silico model finding an additive effect of metformin and gefitinib treatment for lung cancer in silico, validated in vitro. To analyze mode-of-action, immune therapies such as trispecific T-cell engagers in leukemia, as well as toxicity on non-cancer cells, the model can be modularly enriched with human endothelial cells (hECs), immune cells and fibroblasts. Upon addition of hECs, transmigration of immune cells through the endothelial barrier can be investigated. In an allogenic CRC model we observe a lower basic apoptosis rate after applying PBMCs in 3D compared to 2D, which offers new options to mirror antigen-specific immunotherapies in vitro. In conclusion, we present modular human 3D tumor models with tissue-like features for preclinical testing to reduce animal experiments.
KW  - modular tumor tissue models
KW  - invasiveness
KW  - bioreactor culture
KW  - combinatorial drug predictions
KW  - immunotherapies
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231465
VL  - 38
ER  -