Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures
(2015) In European Respiratory Journal 46(4). p.1150-1166- 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... (More)
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.
(Less)
- author
- Uhl, Franziska E. LU ; Vierkotten, Sarah ; Wagner, Darcy E. LU ; Burgstaller, Gerald ; Costa, Ana Rita ; Koch, Ina ; Lindner, Michael ; Meiners, Silke ; Eickelberg, Oliver and Königshoff, Melanie
- publishing date
- 2015-10-01
- type
- Contribution to journal
- publication status
- published
- in
- European Respiratory Journal
- volume
- 46
- issue
- 4
- pages
- 1150 - 1166
- publisher
- European Respiratory Society
- external identifiers
-
- scopus:84939531447
- ISSN
- 0903-1936
- DOI
- 10.1183/09031936.00183214
- language
- English
- LU publication?
- no
- id
- 8f6b342f-1cfe-49fe-81fa-de2768c25270
- date added to LUP
- 2017-08-15 15:02:09
- date last changed
- 2022-03-09 05:21:08
@article{8f6b342f-1cfe-49fe-81fa-de2768c25270, abstract = {{<p>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.</p>}}, author = {{Uhl, Franziska E. and Vierkotten, Sarah and Wagner, Darcy E. and Burgstaller, Gerald and Costa, Ana Rita and Koch, Ina and Lindner, Michael and Meiners, Silke and Eickelberg, Oliver and Königshoff, Melanie}}, issn = {{0903-1936}}, language = {{eng}}, month = {{10}}, number = {{4}}, pages = {{1150--1166}}, publisher = {{European Respiratory Society}}, series = {{European Respiratory Journal}}, title = {{Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures}}, url = {{http://dx.doi.org/10.1183/09031936.00183214}}, doi = {{10.1183/09031936.00183214}}, volume = {{46}}, year = {{2015}}, }