Hachim, MY;
Elemam, NM;
Ramakrishnan, RK;
Bajbouj, K;
Olivenstein, R;
Hachim, IY;
Al Heialy, S;
... Hamoudi, R; + view all
(2021)
Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts.
Frontiers in Cell and Developmental Biology
, 9
, Article 641404. 10.3389/fcell.2021.641404.
Preview |
Text
fcell-09-641404.pdf - Published Version Download (17MB) | Preview |
Abstract
Both canonical and non-canonical Wnt signaling pathway alterations have been documented in pulmonary disease pathogenesis and progression; therefore, they can be an attractive target for pharmaceutical management of severe asthma. Wnt/β-catenin signaling was shown to link early embryonic lung development impairment to later in life asthmatic airway remodeling. Here we explored the changes in Wnt signaling associated with asthma initiation and progression in epithelial and fibroblasts using a comprehensive approach based on in silico analysis and followed by in vitro validation. In summary, the in silico analysis showed that the bronchial epithelium of severe asthmatic patients showed a deranged balance between Wnt enhancer and Wnt inhibitors. A Th2-high phenotype is associated with upregulated Wnt-negative regulators, while inflammatory and neutrophilic severe asthmatics showed higher canonical Wnt signaling member enrichment. Most of these genes are regulators of healthy lung development early in life and, if disturbed, can make people susceptible to developing asthma early in life and prone to developing a severe phenotype. Most of the Wnt members are secreted, and their effect can be in an autocrine fashion on the bronchial epithelium, paracrine on nearby adjacent structural cells like fibroblasts and smooth muscles, or systemic in blood. Our results showed that canonical Wnt signaling is needed for the proper response of cells to proliferative stimuli, which puts cells under stress. Cells in response to this proliferative stress will activate the senescence mechanism, which is also dependent on Wnt signaling. Inhibition of Wnt signaling using FH535 inhibits both proliferation and senescence markers in bronchial fibroblasts compared to DMSO-treated cells. In fibroblasts from asthmatic patients, inhibition of Wnt signaling did not show that effect as the Wnt signaling is deranged besides other pathways that might be non-functional.
| Type: | Article |
|---|---|
| Title: | Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fcell.2021.641404 |
| Publisher version: | https://doi.org/10.3389/fcell.2021.641404 |
| Language: | English |
| Additional information: | Copyright © 2021 Hachim, Elemam, Ramakrishnan, Bajbouj, Olivenstein, Hachim, Al Heialy, Hamid, Busch and Hamoudi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | asthma, Wnt/b-catenin, remodeling, in silco analysis, transcriptome |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10148993 |
Archive Staff Only
 |
View Item |
