RT Journal Article
SR Electronic
T1 Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1150
OP 1166
DO 10.1183/09031936.00183214
VO 46
IS 4
A1 Uhl, Franziska E.
A1 Vierkotten, Sarah
A1 Wagner, Darcy E.
A1 Burgstaller, Gerald
A1 Costa, Rita
A1 Koch, Ina
A1 Lindner, Michael
A1 Meiners, Silke
A1 Eickelberg, Oliver
A1 Königshoff, Melanie
YR 2015
UL http://erj.ersjournals.com/content/46/4/1150.abstract
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