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| Status |
Public on Dec 19, 2023 |
| Title |
Vascular endothelial cells drive organ fibrosis by inducing the transcription factor Sox9 (bulk RNA-Seq IV) |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Chronic fibrosis is a hallmark of pathologic tissue remodelling that deteriorates organ function and eventually leads to death. Although fibroblasts are typically made responsible, it was recently suggested that endothelial cells contribute to fibrosis, although the functional importance of this phenomenon remained unclear. In this study, we addressed this question by genetic manipulation of the fibrogenic HMG-box transcription factor SOX9 specifically in vascular endothelial cells. Induced transgenic overexpression of SOX9 in these cells in mice triggered extensive fibrosis, organ growth and dysfunction in the heart, lung, liver and spleen. We found an upregulation of endogenous Sox9 in endothelial cells during cardiac, lung and liver fibrosis, and endothelial specific Sox9 deletion prevented fibrosis and organ dysfunction in mouse models of systolic and diastolic heart failure, as well as in mouse bleomycin induced pulmonary and non-alcoholic steato-hepatitis (NASH) triggered liver fibrosis. Mechanistically, a combined approach of bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that Sox9 promoted the expression of extracellular matrix and matrix remodelling genes, growth factors, and inflammatory mediators, which triggered the expression of extracellular matrix directly by endothelial cells, but also activated fibroblasts. As we found the upregulation of endothelial Sox9 also in failing human hearts, we propose that endothelial Sox9 could be a target for anti-fibrotic therapy.
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| Overall design |
Liver EC lysates from mice with CDAA diet after endothelial Sox9 knock-out
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| Contributor(s) |
Trogisch FA, Cordero J, Keles M, Heineke J |
| Citation(s) |
38416842 |
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| Submission date |
Mar 07, 2022 |
| Last update date |
Mar 05, 2024 |
| Contact name |
Joerg Heineke |
| E-mail(s) |
[email protected]
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| Organization name |
Medizinische Fakultät Mannheim
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| Department |
– Department of Cardiovascular Research (HKF)
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| Street address |
Ludolf-Krehl-Str. 7-11
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| City |
Mannheim |
| State/province |
Baden Wuttemberg |
| ZIP/Postal code |
68167 |
| Country |
Germany |
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| Platforms (1) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE198041 |
Vascular endothelial cells drive organ fibrosis by inducing the transcription factor Sox9 |
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| Relations |
| BioProject |
PRJNA813506 |
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