Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Zamani M

PROVIDER: S-EPMC9937733 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Zamani Maedeh M Cheng Yu-Hao YH Charbonier Frank F Gupta Vivek Kumar VK Mayer Aaron T AT Trevino Alexandro E AE Quertermous Thomas T Chaudhuri Ovijit O Cahan Patrick P Huang Ngan F NF

Advanced functional materials 20220912 47

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 ...[more]

PMID: 36816792

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Project description:The extracellular matrix was originally thought of as simply a cellular scaffold but is now considered a key regulator of cell function and phenotype from which cells can derive biochemical and mechanical stimuli. Age-associated changes in matrix composition drive increases in matrix stiffness. Enhanced matrix stiffness promotes the progression of numerous diseases including cardiovascular disease, musculoskeletal disease, fibrosis, and cancer. Macrovascular endothelial cells undergo endothelial dysfunction in response to enhanced matrix stiffness. However, endothelial cells are highly heterogeneous, adopting structural and gene expression profiles specific to their organ of origin. Endothelial cells isolated from different vessels (i.e. arteries, veins or capillaries) respond differently to changes in substrate stiffness. It is unknown whether microvascular endothelial cells isolated from different organs also display organ-specific responses to substrate stiffness. In this study, we compare the response of microvascular endothelial cells isolated from both the mouse lung and mammary gland to a range of physiologically relevant substrate stiffnesses. We find that endothelial origin influences microvascular endothelial cell response to substrate stiffness in terms of both proliferation and migration speed. In lung-derived endothelial cells, proliferation is bimodal, where both physiologically soft and stiff substrates drive enhanced proliferation. Conversely, in mammary gland-derived endothelial cells, proliferation increases as substrate stiffness increases. Substrate stiffness also promotes enhanced endothelial migration. Enhanced stiffness drove greater increases in migration speed in mammary gland-derived than lung-derived endothelial cells. However, stiffness-induced changes in microvascular endothelial cell morphology were consistent between both cell lines, with substrate stiffness driving an increase in endothelial volume. Our research demonstrates the importance of considering endothelial origin in experimental design, especially when investigating how age-associated changes in matrix stiffness drive endothelial dysfunction and disease progression.

Dataset Information

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

Publications

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

Similar Datasets

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