Abstract
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 (percent 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.
Abstract
Patient-derived 3D-LTCs are a powerful tool for preclinical drug validation and imaging of Wnt-induced lung repair http://ow.ly/L7BCe
Footnotes
This article has supplementary material available from erj.ersjournals.com
Support statement: This study was supported by a European Research Council Starting Grant to M. Königshoff (ERC-2010-StG 261302) and the Junior Research Group Programme (Helmholtz Association, Berlin, Germany). D.E. Wagner is supported by a Whitaker International Scholar Fellowship and the Helmholtz Munich Postdoctoral Programme. Funding information for this article has been deposited with FundRef.
Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com
- Received October 3, 2014.
- Accepted March 22, 2015.
- Copyright ©ERS 2015