Endothelial cells drive organ fibrosis and dysfunction by inducing the transcription factor SOX9 (ATAC-Seq)
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ABSTRACT:
PROVIDER: PRJNA1057301 | ENA |
REPOSITORIES: ENA
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Project description:Endothelial cells drive organ fibrosis and dysfunction by inducing the transcription factor SOX9 (CUTNTAG)
| PRJNA1057300 | ENA
Project description:Vascular endothelial cells drive organ fibrosis by inducing the transcription factor Sox9
| PRJNA813510 | ENA
Project description:Fibrosis is a hallmark of chronic disease. Although fibroblasts are known to be involved, it is unclear to what extent endothelial cells might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells of fibrotic mouse organs in models of systolic heart failure by pressure overload, diastolic heart failure by high-fat diet and L-Name administration, pulmonary fibrosis after bleomycin treatment, and liver fibrosis as consequence of CDAA diet. We also observed endothelial SOX9 upregulation in human heart tissue in patients with heart failure. To test whether this SOX9 induction was sufficient to cause disease, we generated mice with endothelial cell-specific overexpression of Sox9, which indeed triggered extensive fibrosis in multiple organs and promoted signs of heart failure. Endothelial Sox9 deletion, in turn, prevented fibrosis and organ dysfunction in pre-clinical surgical and pharmacological mouse models of heart failure as well as of lung, and liver injury. Bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that SOX9 induced extracellular matrix, growth factor, and inflammatory genes leading to matrix deposition by endothelial cells. Moreover, in part through triggering an increased expression of the secreted growth factor Ccn2 as direct SOX9 target, endothelial cells activated neighboring fibroblasts to migrate and deposit matrix in response to SOX9. Endothelial Sox9 deletion reversed these changes, suggesting a role for endothelial SOX9 as fibrosis-promoting transcription factor across organs in response to disease stimuli. Therefore, endothelial cells could be a promising target to counteract fibrotic heart, liver and lung disease
2023-12-29 | GSE252082 | GEO
Project description:Fibrosis is a hallmark of chronic disease. Although fibroblasts are known to be involved, it is unclear to what extent endothelial cells might contribute. We detected increased expression of the transcription factor Sox9 in endothelial cells of fibrotic mouse organs in models of systolic heart failure by pressure overload, diastolic heart failure by high-fat diet and L-Name administration, pulmonary fibrosis after bleomycin treatment, and liver fibrosis as consequence of CDAA diet. We also observed endothelial SOX9 upregulation in human heart tissue in patients with heart failure. To test whether this SOX9 induction was sufficient to cause disease, we generated mice with endothelial cell-specific overexpression of Sox9, which indeed triggered extensive fibrosis in multiple organs and promoted signs of heart failure. Endothelial Sox9 deletion, in turn, prevented fibrosis and organ dysfunction in pre-clinical surgical and pharmacological mouse models of heart failure as well as of lung, and liver injury. Bulk and single cell RNA sequencing of endothelial cells across multiple vascular beds revealed that SOX9 induced extracellular matrix, growth factor, and inflammatory genes leading to matrix deposition by endothelial cells. Moreover, in part through triggering an increased expression of the secreted growth factor Ccn2 as direct SOX9 target, endothelial cells activated neighboring fibroblasts to migrate and deposit matrix in response to SOX9. Endothelial Sox9 deletion reversed these changes, suggesting a role for endothelial SOX9 as fibrosis-promoting transcription factor across organs in response to disease stimuli. Therefore, endothelial cells could be a promising target to counteract fibrotic heart, liver and lung disease
2023-12-29 | GSE252081 | GEO
Project description: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.
2023-12-19 | GSE198040 | GEO
Project description: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.
2023-12-19 | GSE198039 | GEO
Project description: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.
2023-12-19 | GSE198034 | GEO
Project description: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.
2023-12-19 | GSE198038 | GEO
Project description: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.
2023-12-19 | GSE198036 | GEO
Project description: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.
2023-12-19 | GSE198035 | GEO