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

Area of Science:

• Cardiovascular Biology
• Cellular Plasticity
• Biomaterials Science

Background:

• Endothelial cell (EC) plasticity, particularly endothelial-mesenchymal transition (EndMT), contributes to atherosclerosis.
• Arterial stiffening is linked to atherosclerosis, but the direct impact of extracellular matrix (ECM) stiffness on EndMT in vivo remains unclear.

Purpose of the Study:

• To investigate the regulatory effects of ECM stiffness on EndMT using an in vitro model.
• To characterize the single-cell transcriptional programs underlying EC plasticity under varying stiffness conditions.

Main Methods:

• Cultured human coronary artery ECs on substrates with physiological and pathological stiffness.
• Utilized single-cell RNA sequencing and trajectory inference analyses.

Main Results:

• Mesenchymal transcriptional features were more prevalent in ECs cultured on pathological stiffness substrates.
• Pathological stiffness blocked a novel mesenchymal-to-endothelial reverse transition.
• ECs exhibiting mesenchymal characteristics on pathological substrates showed transcriptional signatures of atherosclerotic ECs.

Conclusions:

• ECM stiffness significantly influences EC plasticity and promotes EndMT.
• Pathological stiffness impedes ECs' ability to revert from a mesenchymal state, exacerbating atherosclerotic processes.
• This study provides a single-cell resolution resource for understanding EC plasticity in atherosclerosis.