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  - 
TY  - JOUR
A1  - Raselli, Tina
A1  - Hearn, Tom
A1  - Wyss, Annika
A1  - Atrott, Kirstin
A1  - Peter, Alain
A1  - Frey-Wagner, Isabelle
A1  - Spalinger, Marianne R.
A1  - Maggio, Ewerton M.
A1  - Sailer, Andreas W.
A1  - Schmitt, Johannes
A1  - Schreiner, Philipp
A1  - Moncsek, Anja
A1  - Mertens, Joachim
A1  - Scharl, Michael
A1  - Griffiths, William J.
A1  - Bueter, Marco
A1  - Geier, Andreas
A1  - Rogler, Gerhard
A1  - Wang, Yuqin
A1  - Misselwitz, Benjamin
T1  - Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
JF  - Journal of Lipid Research
N2  - Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7 alpha,25-dihydroxycholesterol (7 alpha,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7 alpha,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2(-/-) mice and mice with defects in the 7 alpha,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7 alpha-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.
KW  - nonalcoholic fatty liver disease
KW  - Epstein-Barr virus-induced gene 2
KW  - cholesterol 25 hydroxylase
KW  - 25-hydroxycholesterol 7 alpha-hydroxylase
KW  - mouse feeding model
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225004
VL  - 60
IS  - 7
ER  -