Glypican-3 is a key tuner of the Hedgehog pathway in COPD
Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It orchestrates airway epithelial cell (AEC) differentiation and contributes to respiratory pathogenesis. The core elements Gli2, Smo, and Shh were found altered in the bronchial epithelium of patients with chronic obst...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Heliyon |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024175950 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841533286023692288 |
|---|---|
| author | Laure M.G. Petit Lynda Saber Cherif Maëva A. Devilliers Sarah Hatoum Julien Ancel Gonzague Delepine Anne Durlach Xavier Dubernard Jean-Claude Mérol Christophe Ruaux Myriam Polette Gaëtan Deslée Jeanne-Marie Perotin Valérian Dormoy |
| author_facet | Laure M.G. Petit Lynda Saber Cherif Maëva A. Devilliers Sarah Hatoum Julien Ancel Gonzague Delepine Anne Durlach Xavier Dubernard Jean-Claude Mérol Christophe Ruaux Myriam Polette Gaëtan Deslée Jeanne-Marie Perotin Valérian Dormoy |
| author_sort | Laure M.G. Petit |
| collection | DOAJ |
| description | Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It orchestrates airway epithelial cell (AEC) differentiation and contributes to respiratory pathogenesis. The core elements Gli2, Smo, and Shh were found altered in the bronchial epithelium of patients with chronic obstructive pulmonary disease (COPD). Here, we investigated the co-receptors to fully decipher the complex machinery of airway HH pathway activation in health and COPD. The core elements and co-receptors of HH signalling were investigated in lung cell populations using single-cell RNAseq analysis. The transcript levels of the principal co-receptor GPC3 were investigated on public RNAseq datasets and by RT-qPCR. The localisation of GPC3 was evaluated through immunofluorescent stainings on isolated bronchial AEC and tissues from non-COPD and COPD patients. GPC3 pharmacological modulation was achieved with Codrituzumab during AEC differentiation. We demonstrated that the core elements were not abundant in pulmonary cell populations. Focusing on co-receptors, GPC3 was the most expressed transcript in tracheobronchial epithelial cells. The decrease in GPC3 transcript levels correlated with the severity of airway obstrution in COPD patients. Finally, interfering with GPC3 signalling during AEC differentiation induced downregulation of the HH pathway attested by a decrease of Gli2 leading to reduced ciliogenesis and altered mucin production. GPC3 appears as a crucial co-receptor for the HH pathway in the respiratory context. The modulation of GPC3 may represent a novel experimental strategy to tune HH signalling in therapeutic perspectives. |
| format | Article |
| id | doaj-art-1a94ff9a263443e8a8c8d5f0a8272e28 |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-1a94ff9a263443e8a8c8d5f0a8272e282025-01-17T04:51:39ZengElsevierHeliyon2405-84402025-01-01111e41564Glypican-3 is a key tuner of the Hedgehog pathway in COPDLaure M.G. Petit0Lynda Saber Cherif1Maëva A. Devilliers2Sarah Hatoum3Julien Ancel4Gonzague Delepine5Anne Durlach6Xavier Dubernard7Jean-Claude Mérol8Christophe Ruaux9Myriam Polette10Gaëtan Deslée11Jeanne-Marie Perotin12Valérian Dormoy13Université de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, FranceUniversité de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, FranceUniversité de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, FranceUniversité de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, FranceUniversité de Reims Champagne-Ardenne, INSERM, CHU de Reims, P3Cell UMR-S1250, Reims, FranceUniversité de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, FranceUniversité de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, FranceUniversité de Reims Champagne-Ardenne, CHU de Reims, Reims, FranceUniversité de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, FranceClinique Mutualiste La Sagesse, Département d’Otorhinolaryngologie, Rennes, FranceUniversité de Reims Champagne-Ardenne, INSERM, CHU de Reims, P3Cell UMR-S1250, Reims, FranceUniversité de Reims Champagne-Ardenne, INSERM, CHU de Reims, P3Cell UMR-S1250, Reims, FranceUniversité de Reims Champagne-Ardenne, INSERM, CHU de Reims, P3Cell UMR-S1250, Reims, FranceUniversité de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, France; Corresponding author. Inserm UMR-S 1250 University of Reims Champagne-Ardenne CHU Maison, Blanche 45 rue Cognacq-Jay 51092, Reims, France.Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It orchestrates airway epithelial cell (AEC) differentiation and contributes to respiratory pathogenesis. The core elements Gli2, Smo, and Shh were found altered in the bronchial epithelium of patients with chronic obstructive pulmonary disease (COPD). Here, we investigated the co-receptors to fully decipher the complex machinery of airway HH pathway activation in health and COPD. The core elements and co-receptors of HH signalling were investigated in lung cell populations using single-cell RNAseq analysis. The transcript levels of the principal co-receptor GPC3 were investigated on public RNAseq datasets and by RT-qPCR. The localisation of GPC3 was evaluated through immunofluorescent stainings on isolated bronchial AEC and tissues from non-COPD and COPD patients. GPC3 pharmacological modulation was achieved with Codrituzumab during AEC differentiation. We demonstrated that the core elements were not abundant in pulmonary cell populations. Focusing on co-receptors, GPC3 was the most expressed transcript in tracheobronchial epithelial cells. The decrease in GPC3 transcript levels correlated with the severity of airway obstrution in COPD patients. Finally, interfering with GPC3 signalling during AEC differentiation induced downregulation of the HH pathway attested by a decrease of Gli2 leading to reduced ciliogenesis and altered mucin production. GPC3 appears as a crucial co-receptor for the HH pathway in the respiratory context. The modulation of GPC3 may represent a novel experimental strategy to tune HH signalling in therapeutic perspectives.http://www.sciencedirect.com/science/article/pii/S2405844024175950COPDAirway epithelial cellsHedgehogGPC3 |
| spellingShingle | Laure M.G. Petit Lynda Saber Cherif Maëva A. Devilliers Sarah Hatoum Julien Ancel Gonzague Delepine Anne Durlach Xavier Dubernard Jean-Claude Mérol Christophe Ruaux Myriam Polette Gaëtan Deslée Jeanne-Marie Perotin Valérian Dormoy Glypican-3 is a key tuner of the Hedgehog pathway in COPD Heliyon COPD Airway epithelial cells Hedgehog GPC3 |
| title | Glypican-3 is a key tuner of the Hedgehog pathway in COPD |
| title_full | Glypican-3 is a key tuner of the Hedgehog pathway in COPD |
| title_fullStr | Glypican-3 is a key tuner of the Hedgehog pathway in COPD |
| title_full_unstemmed | Glypican-3 is a key tuner of the Hedgehog pathway in COPD |
| title_short | Glypican-3 is a key tuner of the Hedgehog pathway in COPD |
| title_sort | glypican 3 is a key tuner of the hedgehog pathway in copd |
| topic | COPD Airway epithelial cells Hedgehog GPC3 |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024175950 |
| work_keys_str_mv | AT lauremgpetit glypican3isakeytunerofthehedgehogpathwayincopd AT lyndasabercherif glypican3isakeytunerofthehedgehogpathwayincopd AT maevaadevilliers glypican3isakeytunerofthehedgehogpathwayincopd AT sarahhatoum glypican3isakeytunerofthehedgehogpathwayincopd AT julienancel glypican3isakeytunerofthehedgehogpathwayincopd AT gonzaguedelepine glypican3isakeytunerofthehedgehogpathwayincopd AT annedurlach glypican3isakeytunerofthehedgehogpathwayincopd AT xavierdubernard glypican3isakeytunerofthehedgehogpathwayincopd AT jeanclaudemerol glypican3isakeytunerofthehedgehogpathwayincopd AT christopheruaux glypican3isakeytunerofthehedgehogpathwayincopd AT myriampolette glypican3isakeytunerofthehedgehogpathwayincopd AT gaetandeslee glypican3isakeytunerofthehedgehogpathwayincopd AT jeannemarieperotin glypican3isakeytunerofthehedgehogpathwayincopd AT valeriandormoy glypican3isakeytunerofthehedgehogpathwayincopd |