Biochemical and transcriptomic evaluation of a 3D lung organoid platform for pre-clinical testing of active substances targeting senescence
Abstract Chronic lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis are incurable. Epithelial senescence, a state of dysfunctional cell cycle arrest, contributes to the progression of such diseases. Therefore, lung epithelial cells are a valuable target for therapeutic i...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Respiratory Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12931-023-02636-7 |
| _version_ | 1797362906995621888 |
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| author | Michelle Brand Felix Ritzmann Kathrin Kattler Deivydas Milasius Yiwen Yao Christian Herr Susanne H. Kirsch Rolf Müller Daniela Yildiz Robert Bals Christoph Beisswenger |
| author_facet | Michelle Brand Felix Ritzmann Kathrin Kattler Deivydas Milasius Yiwen Yao Christian Herr Susanne H. Kirsch Rolf Müller Daniela Yildiz Robert Bals Christoph Beisswenger |
| author_sort | Michelle Brand |
| collection | DOAJ |
| description | Abstract Chronic lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis are incurable. Epithelial senescence, a state of dysfunctional cell cycle arrest, contributes to the progression of such diseases. Therefore, lung epithelial cells are a valuable target for therapeutic intervention. Here, we present a 3D airway lung organoid platform for the preclinical testing of active substances with regard to senescence, toxicity, and inflammation under standardized conditions in a 96 well format. Senescence was induced with doxorubicin and measured by activity of senescence associated galactosidase. Pharmaceutical compounds such as quercetin antagonized doxorubicin-induced senescence without compromising organoid integrity. Using single cell sequencing, we identified a subset of cells expressing senescence markers which was decreased by quercetin. Doxorubicin induced the expression of detoxification factors specifically in goblet cells independent of quercetin. In conclusion, our platform enables for the analysis of senescence-related processes and will allow the pre-selection of a wide range of compounds (e.g. natural products) in preclinical studies, thus reducing the need for animal testing. |
| first_indexed | 2024-03-08T16:14:09Z |
| format | Article |
| id | doaj.art-40f13958fbe549e69cbc0aaf61ef4af3 |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-03-08T16:14:09Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-40f13958fbe549e69cbc0aaf61ef4af32024-01-07T12:41:17ZengBMCRespiratory Research1465-993X2024-01-0125111310.1186/s12931-023-02636-7Biochemical and transcriptomic evaluation of a 3D lung organoid platform for pre-clinical testing of active substances targeting senescenceMichelle Brand0Felix Ritzmann1Kathrin Kattler2Deivydas Milasius3Yiwen Yao4Christian Herr5Susanne H. Kirsch6Rolf Müller7Daniela Yildiz8Robert Bals9Christoph Beisswenger10Department of Internal Medicine V – Pulmonology, Allergology and Critical Care Medicine, Saarland UniversityDepartment of Internal Medicine V – Pulmonology, Allergology and Critical Care Medicine, Saarland UniversityDepartment of Genetics/Epigenetics, Saarland UniversityDepartment of Internal Medicine V – Pulmonology, Allergology and Critical Care Medicine, Saarland UniversityDepartment of Internal Medicine V – Pulmonology, Allergology and Critical Care Medicine, Saarland UniversityDepartment of Internal Medicine V – Pulmonology, Allergology and Critical Care Medicine, Saarland UniversityDepartment of Microbial Natural Products (MINS), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University CampusDepartment of Microbial Natural Products (MINS), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University CampusExperimental and Clinical Pharmacology and Toxicology, PZMS, and Center for Human and Molecular Biology (ZHMB), Saarland UniversityDepartment of Internal Medicine V – Pulmonology, Allergology and Critical Care Medicine, Saarland UniversityDepartment of Internal Medicine V – Pulmonology, Allergology and Critical Care Medicine, Saarland UniversityAbstract Chronic lung diseases such as chronic obstructive pulmonary disease and cystic fibrosis are incurable. Epithelial senescence, a state of dysfunctional cell cycle arrest, contributes to the progression of such diseases. Therefore, lung epithelial cells are a valuable target for therapeutic intervention. Here, we present a 3D airway lung organoid platform for the preclinical testing of active substances with regard to senescence, toxicity, and inflammation under standardized conditions in a 96 well format. Senescence was induced with doxorubicin and measured by activity of senescence associated galactosidase. Pharmaceutical compounds such as quercetin antagonized doxorubicin-induced senescence without compromising organoid integrity. Using single cell sequencing, we identified a subset of cells expressing senescence markers which was decreased by quercetin. Doxorubicin induced the expression of detoxification factors specifically in goblet cells independent of quercetin. In conclusion, our platform enables for the analysis of senescence-related processes and will allow the pre-selection of a wide range of compounds (e.g. natural products) in preclinical studies, thus reducing the need for animal testing.https://doi.org/10.1186/s12931-023-02636-7Lung diseasesOrganoidSenescenceToxicityInflammationPreclinical studies |
| spellingShingle | Michelle Brand Felix Ritzmann Kathrin Kattler Deivydas Milasius Yiwen Yao Christian Herr Susanne H. Kirsch Rolf Müller Daniela Yildiz Robert Bals Christoph Beisswenger Biochemical and transcriptomic evaluation of a 3D lung organoid platform for pre-clinical testing of active substances targeting senescence Respiratory Research Lung diseases Organoid Senescence Toxicity Inflammation Preclinical studies |
| title | Biochemical and transcriptomic evaluation of a 3D lung organoid platform for pre-clinical testing of active substances targeting senescence |
| title_full | Biochemical and transcriptomic evaluation of a 3D lung organoid platform for pre-clinical testing of active substances targeting senescence |
| title_fullStr | Biochemical and transcriptomic evaluation of a 3D lung organoid platform for pre-clinical testing of active substances targeting senescence |
| title_full_unstemmed | Biochemical and transcriptomic evaluation of a 3D lung organoid platform for pre-clinical testing of active substances targeting senescence |
| title_short | Biochemical and transcriptomic evaluation of a 3D lung organoid platform for pre-clinical testing of active substances targeting senescence |
| title_sort | biochemical and transcriptomic evaluation of a 3d lung organoid platform for pre clinical testing of active substances targeting senescence |
| topic | Lung diseases Organoid Senescence Toxicity Inflammation Preclinical studies |
| url | https://doi.org/10.1186/s12931-023-02636-7 |
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