A transcriptomic atlas of drug-induced endothelial dysfunction in human endothelial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE217898 | GEO | 2022/11/21
REPOSITORIES: GEO
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Project description:An early aspect of sepsis is dysregulated activation of endothelial cells (EC), initiating a cascade of inflammatory signaling leading to leukocyte adhesion/migration and organ damage. Therapeutic targeting of ECs has been hampered by concerns regarding ECs heterogeneity from different organs. Using a combination of in vitro and in silico analysis, we present a comprehensive analysis of proteomic changes in mouse lung, kidney and liver ECs following exposure to a clinically relevant cocktail of proinflammatory cytokines. Mouse lung, liver and kidney ECs were incubated with TNFα/IL-1β/IFNγ for 4 or 24 hrs to model inflammatory responses during sepsis. Quantitative label-free global proteomics was performed on the ECs to identify differentially expressed proteins (DEP). Proteins with an abundance ratio >2.0 or <0.5 and an adjusted p<0.05 were characterized as upregulated or downregulated respectively. Gene Ontology (GO) classification was used to determine biological processes that regulate EC function during sepsis and PANTHER was used to classify the molecular function of the identified proteins. Finally, an interactive pathway was developed to investigate signaling within ECs and across organs. Proteomic analysis identified both unique and shared DEPs between the ECs specific to lung, liver and kidney. Using GO, 5 Biological Processes (BP) for each of the organ specific ECs were identified. Interestingly, 4 of the top 5 GO BPs were observed in all 3 ECs at 4 and 24 hrs: defense response to other organism, innate immune response, response to bacterium and response to cytokine. However, these BPs were found to be differentially regulated. For example, at 4 and 24 hrs, lung ECs which have the highest number and highest fold expression of upregulated proteins (189 and 316 respectively), also have higher numbers of unique upregulated proteins (124 vs 194) compared to liver (98 vs 121) and kidney ECs (109 vs 136). The liver showed the greatest number of conserved proteins between 4 and 24 hrs (56) compared to lung (50) and kidney (51). The number of common proteins between all three ECs increases from 38 at 4 hrs to 79 at 24 hrs, indicating more uniformity in ECs proteomic expression during the progression of sepsis. The PANTHER database was used to classify proteins in different functional groups (e.g. defense/immunity) at 4 and 24 hrs. Thus, BPs and PANTHER hits can provide insight into why some organs are more susceptible to sepsis early on and show that as sepsis progresses, some protein expression patterns become more uniform while additional organ specific proteins are expressed. Proteomic analysis of organ-specific ECs provides further understanding of how sepsis affects multiple organs across time and supports future proteomic, temporal studies of EC dysfunction.
2022-10-14 | PXD031804 | Pride
Project description:Diabetes is a known risk factor for various cardiovascular complications, mediated by endothelial dysfunction. Despite the high prevalence of this metabolic disorder, there is a lack of in vitro models that recapitulate the complexity of genetic and environmental factors associated with diabetic endothelial dysfunction. Here, we utilized human induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) to develop in vitro models of diabetic endothelial dysfunction. We found that the diabetic phenotype was recapitulated in diabetic patient-derived iPSC-ECs, even in the absence of a diabetogenic environment. Subsequent exposure with culture conditions that mimic the diabetic clinical chemistry induced a diabetic phenotype in healthy iPSC-ECs but did not affect the already dysfunctional diabetic iPSC-ECs. RNA-seq analysis revealed extensive transcriptome-wide differences between cells derived from healthy individuals and diabetic patients. The in vitro disease models were used as a screening platform which identified angiotensin receptor blockers (ARBs) that improved endothelial function in vitro for each patient. In summary, we present in vitro models of diabetic endothelial dysfunction using iPSC technology, taking into account the complexity of genetic and environmental factors in the metabolic disorder. Our study provides novel insights into the pathophysiology of diabetic endothelial dysfunction and highlights the potential of iPSC-based models for drug discovery and personalized medicine.
2023-07-05 | GSE236430 | GEO
Project description: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.
2024-08-27 | GSE248489 | GEO
Project description: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.
2024-08-27 | GSE252446 | GEO
Project description: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.
2024-08-27 | GSE252445 | GEO
Project description: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.
2024-08-31 | GSE249111 | GEO
Project description: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.
2024-08-27 | GSE252444 | GEO
Project description: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.
2024-08-31 | GSE227211 | GEO
Project description:Two healthy iPSC lines were differentiated into ECs. iPSC-ECs were then treated under normoglycemic (5.5mM glucose) or hyperglycemic (33mM glucose) conditions with and without MDL-28170 (2.5 uM) for 72 hours.
2019-02-15 | GSE123699 | GEO
Project description:Little is known about the function of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) generated from diabetics, as this could potentially limit subsequent therapeutic use in this patient population. Here, we demonstrate that iPSC-ECs derived from diet-induced obesity (DIO) mice exhibit evidence of endothelial dysfunction. We also observed that mice receiving intramuscular (IM) injections of DIO iPSC-ECs had significantly decreased reperfusion following hindlimb ischemia compared to mice administered with iPSC-ECs from control mice. Hindlimb sections revealed increased muscle atrophy and presence of inflammatory cells in mice receiving iPSC-ECs from DIO mice. When pravastatin was administered to mice receiving DIO iPSC-ECs, a significant increase in reperfusion was observed, which was blunted by co-administration of L-NAME. This study is the first to provide evidence that iPSC-ECs from pre-diabetic mice exhibit signs of endothelial function, and suggest that pravastatin administration may be needed for diabetic patients receiving autologous iPSC-ECs therapy in the clinic. Four samples were analyzed, two from the healthy (control) group and two from the diet-induced obesity group
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