Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoids
Abstract Regeneration of the alveolar epithelium is necessary to restore tissue architecture and gas exchange capabilities in chronic pulmonary diseases such as fibrosing interstitial lung disease. While it is known alveolar type 2 (AT2) cells give rise to alveolar type 1 (AT1) cells to repair the a...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08446-5 |
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| author | Andrew S. Hagan Scott Williams Casey J. N. Mathison Shanshan Yan Bao Nguyen Glenn C. Federe Guray Kuzu Joseph C. Siefert Janice Hampton Victor Chichkov S. Whitney Barnes Frederick J. King Brandon L. Taylor John R. Walker Rui Zhao Jimmy Elliott Dean P. Phillips Bin Fang Rebekah S. Decker |
| author_facet | Andrew S. Hagan Scott Williams Casey J. N. Mathison Shanshan Yan Bao Nguyen Glenn C. Federe Guray Kuzu Joseph C. Siefert Janice Hampton Victor Chichkov S. Whitney Barnes Frederick J. King Brandon L. Taylor John R. Walker Rui Zhao Jimmy Elliott Dean P. Phillips Bin Fang Rebekah S. Decker |
| author_sort | Andrew S. Hagan |
| collection | DOAJ |
| description | Abstract Regeneration of the alveolar epithelium is necessary to restore tissue architecture and gas exchange capabilities in chronic pulmonary diseases such as fibrosing interstitial lung disease. While it is known alveolar type 2 (AT2) cells give rise to alveolar type 1 (AT1) cells to repair the alveolar epithelium after injury, methods to promote this process under pathological settings are poorly understood. Here, using a complex 3D organoid culture with TGF-β1 dependent impaired AT1 spheroid formation, we performed a high-throughput screen (HTS) with ~16,800 compounds to identify small molecules that increase number of AT1 spheroids. Longitudinal single cell RNA sequencing (scRNA-seq) revealed that DB-11-BE87 increased AT1 regeneration by reducing TGF-β1 induced fibroblast activation, concurrently with AHR activation in those cells. These studies highlight a HTS system to identify factors that can promote AT1 differentiation and suggest AHR activation as a method to counteract pathological TGF-β1 signaling in pulmonary disease. |
| format | Article |
| id | doaj-art-e3046864c62a446caaae50f1aef82c92 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-e3046864c62a446caaae50f1aef82c922025-08-20T04:02:56ZengNature PortfolioCommunications Biology2399-36422025-07-018111510.1038/s42003-025-08446-5Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoidsAndrew S. Hagan0Scott Williams1Casey J. N. Mathison2Shanshan Yan3Bao Nguyen4Glenn C. Federe5Guray Kuzu6Joseph C. Siefert7Janice Hampton8Victor Chichkov9S. Whitney Barnes10Frederick J. King11Brandon L. Taylor12John R. Walker13Rui Zhao14Jimmy Elliott15Dean P. Phillips16Bin Fang17Rebekah S. Decker18Novartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchNovartis Biomedical ResearchAbstract Regeneration of the alveolar epithelium is necessary to restore tissue architecture and gas exchange capabilities in chronic pulmonary diseases such as fibrosing interstitial lung disease. While it is known alveolar type 2 (AT2) cells give rise to alveolar type 1 (AT1) cells to repair the alveolar epithelium after injury, methods to promote this process under pathological settings are poorly understood. Here, using a complex 3D organoid culture with TGF-β1 dependent impaired AT1 spheroid formation, we performed a high-throughput screen (HTS) with ~16,800 compounds to identify small molecules that increase number of AT1 spheroids. Longitudinal single cell RNA sequencing (scRNA-seq) revealed that DB-11-BE87 increased AT1 regeneration by reducing TGF-β1 induced fibroblast activation, concurrently with AHR activation in those cells. These studies highlight a HTS system to identify factors that can promote AT1 differentiation and suggest AHR activation as a method to counteract pathological TGF-β1 signaling in pulmonary disease.https://doi.org/10.1038/s42003-025-08446-5 |
| spellingShingle | Andrew S. Hagan Scott Williams Casey J. N. Mathison Shanshan Yan Bao Nguyen Glenn C. Federe Guray Kuzu Joseph C. Siefert Janice Hampton Victor Chichkov S. Whitney Barnes Frederick J. King Brandon L. Taylor John R. Walker Rui Zhao Jimmy Elliott Dean P. Phillips Bin Fang Rebekah S. Decker Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoids Communications Biology |
| title | Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoids |
| title_full | Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoids |
| title_fullStr | Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoids |
| title_full_unstemmed | Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoids |
| title_short | Triggering AHR resolves TGF-β1 induced fibroblast activation and promotes AT1 cell regeneration in alveolar organoids |
| title_sort | triggering ahr resolves tgf β1 induced fibroblast activation and promotes at1 cell regeneration in alveolar organoids |
| url | https://doi.org/10.1038/s42003-025-08446-5 |
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