Single-cell RNA-seq reveals a critical role of novel pro-inflammatory EndMT in mediating adverse remodeling in coronary artery-on-a-chip.
Single-cell RNA-seq reveals a critical role of novel pro-inflammatory EndMT in mediating adverse remodeling in coronary artery-on-a-chip.
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DOI：
10.1126/sciadv.abg1694
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发表时间：
2021-08
期刊：
影响因子：
13.6
通讯作者：
Meng X
中科院分区：
文献类型：
--
作者：
Zhao P;Yao Q;Zhang PJ;The E;Zhai Y;Ao L;Jarrett MJ;Dinarello CA;Fullerton DA;Meng X
切应力诱导冠状动脉芯片模型中内皮细胞转化为促炎间充质表型。建立了一个三维微工程化的人冠状动脉芯片，用于研究低剪切应力和振荡剪切应力（OSS）诱导致动脉粥样硬化变化的机制。单细胞RNA测序显示，OSS诱导内皮细胞（EC）的明显变化，包括促炎性内皮-间质转化（EndMT）。OSS通过Notch 1/p38 MAPK-NF-κB信号轴促进EndMT的促炎作用。此外，OSS诱导的EC表型变化导致平滑肌细胞（SMCs）增殖和细胞外基质（ECM）蛋白通过RANTES介导的旁分泌机制上调。IL-37抑制OSS诱导的促炎性EndMT，从而消除SMC增殖和ECM蛋白重塑。总的来说，这项研究提供了对动脉粥样硬化剪切力下内皮异质性的深入了解，并确定了一种新的EC亚型在促进不良血管重塑中的机制作用。此外，本研究表明，抗炎方法能够减轻动脉粥样硬化剪切应力诱发的血管病理学。
Shear stress induces endothelial transition to pro-inflammatory mesenchymal phenotype in a coronary artery–on–a–chip model. A three-dimensional microengineered human coronary artery–on–a–chip was developed for investigation of the mechanism by which low and oscillatory shear stress (OSS) induces pro-atherogenic changes. Single-cell RNA sequencing revealed that OSS induced distinct changes in endothelial cells (ECs) including pro-inflammatory endothelial-to-mesenchymal transition (EndMT). OSS promoted pro-inflammatory EndMT through the Notch1/p38 MAPK–NF-κB signaling axis. Moreover, OSS-induced EC phenotypic changes resulted in proliferation and extracellular matrix (ECM) protein up-regulation in smooth muscle cells (SMCs) through the RANTES-mediated paracrine mechanism. IL-37 suppressed OSS-induced pro-inflammatory EndMT and thereby abrogated SMC proliferation and ECM protein remodeling. Overall, this study provides insights into endothelial heterogeneity under atheroprone shear stress and identifies the mechanistic role of a novel EC subtype in promoting adverse vascular remodeling. Further, this study demonstrates that anti-inflammatory approach is capable of mitigating vascular pathobiology evoked by atheroprone shear stress.
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