Endothelial Reprogramming by Disturbed Flow Revealed by Single-Cell RNA and Chromatin Accessibility Study

Andueza, Aitor; Kumar, Sandeep; Kim, Juyoung; Kang, Dong‐Won; Mumme, Hope L; Perez, Julian I.; Villa-Roel, Nicolas; Jo, Hanjoong

doi:10.1016/j.celrep.2020.108491

Cited by 122 publications

(161 citation statements)

References 73 publications

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“…Furthermore, both our study and the endothelial-lineage tracing study similarly demonstrated that ECs which undergo EndMT rarely give rise to vascular smooth muscle cells (VSMCs) in plaques. However, some studies showed that VSMCs or immune cells arise from EndMT in angiogenesis ( Rohlenova et al, 2020 ) or in carotid artery exposed to disturbed flow ( Andueza et al, 2020 ). Unexpectedly, we also identified the presence of EndMT-derived fibroblast-like cells in the Chow group (6.63% EndMT + of total ECs).…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Transcriptomics Reveals Endothelial Plasticity During Diabetic Atherogenesis

Zhao

Liu

et al. 2021

Front. Cell Dev. Biol.

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Atherosclerosis is the leading cause of cardiovascular diseases, which is also the primary cause of mortality among diabetic patients. Endothelial cell (EC) dysfunction is a critical early step in the development of atherosclerosis and aggravated in the presence of concurrent diabetes. Although the heterogeneity of the organ-specific ECs has been systematically analyzed at the single-cell level in healthy conditions, their transcriptomic changes in diabetic atherosclerosis remain largely unexplored. Here, we carried out a single-cell RNA sequencing (scRNA-seq) study using EC-enriched single cells from mouse heart and aorta after 12 weeks feeding of a standard chow or a diabetogenic high-fat diet with cholesterol. We identified eight EC clusters, three of which expressed mesenchymal markers, indicative of an endothelial-to-mesenchymal transition (EndMT). Analyses of the marker genes, pathways, and biological functions revealed that ECs are highly heterogeneous and plastic both in normal and atherosclerotic conditions. The metabolic transcriptomic analysis further confirmed that EndMT-derived fibroblast-like cells are prominent in atherosclerosis, with diminished fatty acid oxidation and enhanced biological functions, including regulation of extracellular-matrix organization and apoptosis. In summary, our data characterized the phenotypic and metabolic heterogeneity of ECs in diabetes-associated atherogenesis at the single-cell level and paves the way for a deeper understanding of endothelial cell biology and EC-related cardiovascular diseases.

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Section: Discussionmentioning

confidence: 99%

Single-Cell Transcriptomics Reveals Endothelial Plasticity During Diabetic Atherogenesis

Zhao

Liu

et al. 2021

Front. Cell Dev. Biol.

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“…Of note, scRNA-seq and ATAC-sequencing (to characterize the epigenomic landscape) of ECs from mouse carotid arteries after partial ligation illustrated that disturbed flow induced reprogramming of ECs toward an immune cell-like phenotype (coined “EndICLT”), expressing macrophage markers [ 100 ]. Tissue-specific endothelial genes (enriched in the brain, heart, lungs, and kidney [ 4 ]) were expressed at low or undetectable level in carotid ECs [ 100 ], further illustrating the tissue- and vascular bed-specific EC heterogeneity. Notably, disturbed flow also induced this EndICLT phenotype in cultured human aortic ECs, in the absence of immune cells [ 100 ].…”

Section: Ec Heterogeneity In Tissue Repairmentioning

confidence: 99%

“…Tissue-specific endothelial genes (enriched in the brain, heart, lungs, and kidney [ 4 ]) were expressed at low or undetectable level in carotid ECs [ 100 ], further illustrating the tissue- and vascular bed-specific EC heterogeneity. Notably, disturbed flow also induced this EndICLT phenotype in cultured human aortic ECs, in the absence of immune cells [ 100 ]. Thus, ECs are highly plastic cells that transition to immunomodulatory cell phenotypes, identifiable by single-cell analysis as a separate subset [ 100 ].…”

Section: Ec Heterogeneity In Tissue Repairmentioning

confidence: 99%

“…Notably, disturbed flow also induced this EndICLT phenotype in cultured human aortic ECs, in the absence of immune cells [ 100 ]. Thus, ECs are highly plastic cells that transition to immunomodulatory cell phenotypes, identifiable by single-cell analysis as a separate subset [ 100 ]. ECs have been previously involved in immune responses [ 101 , 102 ].…”

Section: Ec Heterogeneity In Tissue Repairmentioning

confidence: 99%

“…Emerging multi-omic platforms offer the opportunity to simultaneously profile RNA and DNA and/or protein at the single-cell level and with spatial resolution. Recent examples include scRNA-seq and chromatin accessibility analysis of ECs in a mouse model of disturbed flow [ 100 ] as well as the analysis of the chromatin landscape of cardiac ECs [ 144 ] and brain ECs [ 145 ] . Spatial analyses are also being used to map (endothelial) cell heterogeneity across tissues and conditions including in large cohorts of tissues [ 146 ].…”

mentioning

confidence: 99%

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Endothelial cell plasticity at the single-cell level

et al. 2021

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The vascular endothelium is characterized by a remarkable level of plasticity, which is the driving force not only of physiological repair/remodeling of adult tissues but also of pathological angiogenesis. The resulting heterogeneity of endothelial cells (ECs) makes targeting the endothelium challenging, no less because many EC phenotypes are yet to be identified and functionally inventorized. Efforts to map the vasculature at the single-cell level have been instrumental to capture the diversity of EC types and states at a remarkable depth in both normal and pathological states. Here, we discuss new EC subtypes and functions emerging from recent single-cell studies in health and disease. Interestingly, such studies revealed distinct metabolic gene signatures in different EC phenotypes, which deserve further consideration for therapy. We highlight how this metabolic targeting strategy could potentially be used to promote (for tissue repair) or block (in tumor) angiogenesis in a tissue or even vascular bed-specific manner.

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Single‐Cell Transcriptomic Census of Endothelial Changes Induced by Matrix Stiffness and the Association with Atherosclerosis

Zamani

Cheng

Charbonier

et al. 2022

Adv Funct Materials

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Vascular endothelial cell (EC) plasticity plays a critical role in the progression of atherosclerosis by giving rise to mesenchymal phenotypes in the plaque lesion. Despite the evidence for arterial stiffening as a major contributor to atherosclerosis, the complex interplay among atherogenic stimuli in vivo has hindered attempts to determine the effects of extracellular matrix (ECM) stiffness on endothelial‐mesenchymal transition (EndMT). To study the regulatory effects of ECM stiffness on EndMT, an in vitro model is developed in which human coronary artery ECs are cultured on physiological or pathological stiffness substrates. Leveraging single‐cell RNA sequencing, cell clusters with mesenchymal transcriptional features are identified to be more prevalent on pathological substrates than physiological substrates. Trajectory inference analyses reveal a novel mesenchymal‐to‐endothelial reverse transition, which is blocked by pathological stiffness substrates, in addition to the expected EndMT trajectory. ECs pushed to a mesenchymal character by pathological stiffness substrates are enriched in transcriptional signatures of atherosclerotic ECs from human and murine plaques. This study characterizes at single‐cell resolution the transcriptional programs that underpin EC plasticity in both physiological or pathological milieus, and thus serves as a valuable resource for more precisely defining EndMT and the transcriptional programs contributing to atherosclerosis.

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Endothelial Reprogramming by Disturbed Flow Revealed by Single-Cell RNA and Chromatin Accessibility Study

Cited by 122 publications

References 73 publications

Single-Cell Transcriptomics Reveals Endothelial Plasticity During Diabetic Atherogenesis

Single-Cell Transcriptomics Reveals Endothelial Plasticity During Diabetic Atherogenesis

Endothelial cell plasticity at the single-cell level

Single‐Cell Transcriptomic Census of Endothelial Changes Induced by Matrix Stiffness and the Association with Atherosclerosis

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