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| Status |
Public on Aug 27, 2024 |
| Title |
CCL2-mediated Endothelial Injury Drives Cardiac Dysfunction in Long COVID [tissue] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Chronic endotheliitis and various cardiovascular co-morbidities are more likely to develop in patients who are recovering from a post-acute SARS-CoV-2 infection. Despite a growing body of clinical data suggesting that the endothelium could be the cause of both cardiac injury and the multi-organ damage found in COVID-19 patients, there is no clear link between endothelial (EC) dysfunction and increased cardiac risk during long COVID. Here, we studied long COVID-19-associated endotheliitis and its implications on cardiac dysfunction. Thrombotic vascular tissues from long COVID patients were harvested and profiled to identify the different mechanisms of viral-induced EC pathogenesis. Human induced pluripotent stem cell (iPSC)–derived ECs were leveraged to model endotheliitis in-a-dish after exposure to SARS-CoV-2, which showed similar EC dysfunction and upregulation of specific cytokines such as CCL2 and IL6, as seen in the primary ECs of long COVID patients. 3D fabricated cardiac organoids generated from iPSC-ECs and iPSC-derived cardiomyocytes (iPSC-CMs) were utilized to understand the pathological influence of endotheliitis on cardiac dysfunction. Notably, cardiac dysfunction was observed only in cardiac organoids that were fabricated with both iPSC-CMs and iPSC-ECs after exposure to SARS-CoV-2. Simultaneous profiling of chromatin accessibility and gene expression dynamics via integration of ATAC-seq and RNA-seq at a single cell resolution revealed CCL2 as the prime cytokine responsible for the non-endothelial “phenotype switching” and the impending cardiac dysfunction in cardiac organoids. This was further validated by high-throughput proteomics that showed CCL2 to be released only by cardiac organoids that were fabricated with iPSC-CMs and iPSC-ECs after SARS-CoV-2 infection. Lastly, disease modeling of the cardiac organoids as well as exposure of human ACE2 transgenic mice to SARS-CoV-2 spike proteins uncovered a putative mechanism for the cardiac dysfunction involving posttranslational modification of cardiac proteins driven by oxidative stress and inflammation. These results suggest that EC-released cytokines can contribute to the pathogenesis of long COVID-associated cardiac dysfunction, and thus a thorough clinical profiling of vascular health could help identify early signs of heart disease in COVID-19 patients.
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| Overall design |
Bulk was conducted on long COVID, healthy, and PAD tissues. scRNA-seq was conducted on human arteries that were collected from Long COVID patients that had undergone below-knee amputation. Similarly, scRNA-seq was conducted on arteries collected from NON-COVID patients that suffered from peripherial artery disease (PAD) and undergone below-knee amputation due to complete occlusion of their arteries.
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| Contributor(s) |
Wu D, Sayed N |
| Citation missing |
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| |
| Submission date |
Jan 03, 2024 |
| Last update date |
Aug 27, 2024 |
| Contact name |
Nazish Sayed |
| E-mail(s) |
sayedns@stanford.edu
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| Organization name |
Stanford University
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| Street address |
240 Pasteur Drive, 3500 BMI
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| City |
Palo Alto |
| State/province |
California |
| ZIP/Postal code |
94303 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (9)
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| This SubSeries is part of SuperSeries: |
| GSE252448 |
CCL2-mediated Endothelial Injury Drives Cardiac Dysfunction in Long COVID |
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| Relations |
| BioProject |
PRJNA1060667 |
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