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Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures

Uhl, Franziska E.; Vierkotten, Sarah; Wagner, Darcy E. LU ; Burgstaller, Gerald; Costa, Ana Rita; Koch, Ina; Lindner, Michael; Meiners, Silke; Eickelberg, Oliver and Königshoff, Melanie (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.

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author
publishing date
type
Contribution to journal
publication status
published
in
European Respiratory Journal
volume
46
issue
4
pages
1150 - 1166
publisher
Eur Respiratory Soc
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
2017-09-10 05:22:55
@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    = {Eur Respiratory Soc},
  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},
  volume       = {46},
  year         = {2015},
}