PT  - JOURNAL ARTICLE
AU  - Uhl, Franziska E.
AU  - Vierkotten, Sarah
AU  - Wagner, Darcy E.
AU  - Burgstaller, Gerald
AU  - Costa, Rita
AU  - Koch, Ina
AU  - Lindner, Michael
AU  - Meiners, Silke
AU  - Eickelberg, Oliver
AU  - Königshoff, Melanie
TI  - Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures
AID  - 10.1183/09031936.00183214
DP  - 2015 Oct 01
TA  - European Respiratory Journal
PG  - 1150--1166
VI  - 46
IP  - 4
4099  - http://erj.ersjournals.com/content/46/4/1150.short
4100  - http://erj.ersjournals.com/content/46/4/1150.full
SO  - Eur Respir J2015 Oct 01; 46
AB  - Chronic obstructive pulmonary disease (COPD) is characterised by a progressive loss of lung tissue. Inducing repair processes within the adult diseased lung is of major interest and Wnt/β-catenin signalling represents a promising target for lung repair. However, the translation of novel therapeutic targets from model systems into clinical use remains a major challenge.We generated murine and patient-derived three-dimensional (3D) ex vivo lung tissue cultures (LTCs), which closely mimic the 3D lung microenvironment in vivo. Using two well-known glycogen synthase kinase-3β inhibitors, lithium chloride (LiCl) and CHIR 99021 (CT), we determined Wnt/β-catenin-driven lung repair processes in high spatiotemporal resolution using quantitative PCR, Western blotting, ELISA, (immuno)histological assessment, and four-dimensional confocal live tissue imaging.Viable 3D-LTCs exhibited preserved lung structure and function for up to 5 days. We demonstrate successful Wnt/β-catenin signal activation in murine and patient-derived 3D-LTCs from COPD patients. Wnt/β-catenin signalling led to increased alveolar epithelial cell marker expression, decreased matrix metalloproteinase-12 expression, as well as altered macrophage activity and elastin remodelling. Importantly, induction of surfactant protein C significantly correlated with disease stage (per cent predicted forced expiratory volume in 1 s) in patient-derived 3D-LTCs.Patient-derived 3D-LTCs represent a valuable tool to analyse potential targets and drugs for lung repair. Enhanced Wnt/β-catenin signalling attenuated pathological features of patient-derived COPD 3D-LTCs.Patient-derived 3D-LTCs are a powerful tool for preclinical drug validation and imaging of Wnt-induced lung repair http://ow.ly/L7BCe