Stiffness regulates extracellular matrix synthesis in fibroblasts by DDR1-TGF-β/STAT3 mechanotransduction axis.

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Tác giả: Xiaomei Han, Qian Lei, Jin Xu, Chao Zhang, Yue Zhou

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: Netherlands : Biomaterials advances , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 710640

For a long time, research on atherosclerosis (AS) has mainly focused on endothelial cells (ECs) and smooth muscle cells (SMCs) in blood vessels. Fibroblasts, however, being the major component in adventitia, little is known about their role. Fibroblasts are highly plastic cells, capable of undergoing phenotypic changes in response to various extracellular signals. Once activated, fibroblasts can promote fibrosis by altering the secretion of extracellular matrix (ECM). In this study, the effect of ECM stiffness on fibroblasts was investigated. Polyacrylamide (PA) gels with varying elastic moduli (1 kPa, 20 kPa and 100 kPa) were used as models for matrix stiffness. Human fibroblasts were cultured on these substrates, and their phenotypic and functional changes were examined. The data revealed that a collagen-binding receptor, Discoidin Domain Receptor 1 (DDR1), plays a central role in sensing mechanical stimuli from ECM. Matrix stiffness-induced phosphorylation of DDR1 suppresses the synthesis of ECM proteins in fibroblasts. The expression of ECM proteins on the 1 kPa substrate was significantly higher than that on the 20 kPa and 100 kPa substrates, while the phosphorylation level of DDR1 was notably reduced. After knocking out DDR1, the difference in ECM proteins expression among the three substrates with different stiffness levels disappeared. The signal transduction from DDR1 to ECM synthesis is mediated by the TGF-β/STAT3 signaling axis. Our study reveals how matrix stiffness regulates the synthesis of ECM in fibroblasts and paves the way for understanding the regulation of fibrotic process in the pathogenesis of AS.
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