Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts
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 develo...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2021-03-01
|
| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.641404/full |
| _version_ | 1818700715258806272 |
|---|---|
| author | Mahmood Yaseen Hachim Noha Mousaad Elemam Rakhee K. Ramakrishnan Khuloud Bajbouj Ronald Olivenstein Ibrahim Yaseen Hachim Saba Al Heialy Saba Al Heialy Qutayba Hamid Qutayba Hamid Hauke Busch Rifat Hamoudi Rifat Hamoudi |
| author_facet | Mahmood Yaseen Hachim Noha Mousaad Elemam Rakhee K. Ramakrishnan Khuloud Bajbouj Ronald Olivenstein Ibrahim Yaseen Hachim Saba Al Heialy Saba Al Heialy Qutayba Hamid Qutayba Hamid Hauke Busch Rifat Hamoudi Rifat Hamoudi |
| author_sort | Mahmood Yaseen Hachim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T15:09:21Z |
| format | Article |
| id | doaj.art-6265e5970df9418f895ab53954e8d54b |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-17T15:09:21Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-6265e5970df9418f895ab53954e8d54b2022-12-21T21:43:43ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-03-01910.3389/fcell.2021.641404641404Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and FibroblastsMahmood Yaseen Hachim0Noha Mousaad Elemam1Rakhee K. Ramakrishnan2Khuloud Bajbouj3Ronald Olivenstein4Ibrahim Yaseen Hachim5Saba Al Heialy6Saba Al Heialy7Qutayba Hamid8Qutayba Hamid9Hauke Busch10Rifat Hamoudi11Rifat Hamoudi12College of Medicine, Mohammed bin Rashid University of Medicine and Health Sciences, Dubai, United Arab EmiratesSharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab EmiratesSharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab EmiratesSharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab EmiratesMeakins-Christie Laboratories, McGill University, Montreal, QC, CanadaSharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab EmiratesCollege of Medicine, Mohammed bin Rashid University of Medicine and Health Sciences, Dubai, United Arab EmiratesMeakins-Christie Laboratories, McGill University, Montreal, QC, CanadaSharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab EmiratesMeakins-Christie Laboratories, McGill University, Montreal, QC, CanadaMedical Systems Biology Group, Institute for Experimental Dermatology, Institute for Cardiogenetics, University of Lübeck, Lübeck, GermanySharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab EmiratesDivision of Surgery and Interventional Science, University College London, London, United KingdomBoth 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.641404/fullasthmaWnt/b-cateninremodelingin silco analysistranscriptome |
| spellingShingle | Mahmood Yaseen Hachim Noha Mousaad Elemam Rakhee K. Ramakrishnan Khuloud Bajbouj Ronald Olivenstein Ibrahim Yaseen Hachim Saba Al Heialy Saba Al Heialy Qutayba Hamid Qutayba Hamid Hauke Busch Rifat Hamoudi Rifat Hamoudi Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts Frontiers in Cell and Developmental Biology asthma Wnt/b-catenin remodeling in silco analysis transcriptome |
| title | Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts |
| title_full | Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts |
| title_fullStr | Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts |
| title_full_unstemmed | Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts |
| title_short | Wnt Signaling Is Deranged in Asthmatic Bronchial Epithelium and Fibroblasts |
| title_sort | wnt signaling is deranged in asthmatic bronchial epithelium and fibroblasts |
| topic | asthma Wnt/b-catenin remodeling in silco analysis transcriptome |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.641404/full |
| work_keys_str_mv | AT mahmoodyaseenhachim wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT nohamousaadelemam wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT rakheekramakrishnan wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT khuloudbajbouj wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT ronaldolivenstein wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT ibrahimyaseenhachim wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT sabaalheialy wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT sabaalheialy wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT qutaybahamid wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT qutaybahamid wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT haukebusch wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT rifathamoudi wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts AT rifathamoudi wntsignalingisderangedinasthmaticbronchialepitheliumandfibroblasts |