Dysregulation of interaction between LOX(high) fibroblast and smooth muscle cells contributes to the pathogenesis of aortic dissection.
Dysregulation of interaction between LOX(high) fibroblast and smooth muscle cells contributes to the pathogenesis of aortic dissection.
复制标题
LOXhigh 成纤维细胞和平滑肌细胞之间相互作用的失调导致主动脉夹层的发病机制
作者：
Chen Y;Zhang T;Yao F;Gao X;Li D;Fu S;Mao L;Liu F;Zhang X;Xu Y;Deng J;Li W;Fan G;Xiao C;Chen Y;Wang L;Guo W;Zhou B
基本原理：虽然细胞-细胞相互作用在生理学和疾病中起着关键作用，但对其在血管稳态和疾病中的动力学的全面理解仍然缺乏。研究方法：在这里，通过使用单细胞RNA测序和多色染色，我们描绘了人类主动脉的细胞组成和空间特征与或没有主动脉夹层（AD）。结果：细胞亚型的变化表明，在AD中成纤维细胞（FB）-平滑肌细胞（SMC）的相互作用显着改变。在这些细胞相互作用中，处于患病状态的LOX高成纤维细胞（成纤维细胞亚型2，FB 2）对AD中SMC的病理恶化产生最显著的影响。此外，靶向BMP（骨形态发生蛋白）信号通路的BMP 2有效抑制FB 2状态转换，降低小鼠AD发病率。最后，从FB 2释放的分泌蛋白之一COL 5A 1（胶原V型α 1链）在AD患者的血浆中显著高于对照患者，表明其作为AD诊断的生物标志物的潜在用途。结论：我们的工作不仅确定了一个特定的FB亚型在AD进展中的关键作用，而且还阐明了血管疾病中的细胞相互作用动力学。
Rationale: While cell-cell interaction plays a critical role in physiology and disease, a comprehensive understanding of its dynamics in vascular homeostasis and diseases is yet absent. Methods: Here, by use of single-cell RNA-sequencing and multi-color staining, we delineate the cellular composition and spatial characterization of human aorta with or without aortic dissection (AD). Results: Scrutinization of cell subtype alterations revealed significantly changed fibroblast (FB)-smooth muscle cell (SMC) interactions in AD. Of these cellular interactions, LOXhigh fibroblast (fibroblast subtype 2, FB2) in diseased state exerted the most pronounced effects on pathological deterioration of SMCs in AD. In addition, pharmacologically targeting the BMP (bone morphogenetic protein) signaling pathway effectively suppressed FB2 state transition and reduced AD incidence in mice. Finally, COL5A1 (collagen type V alpha 1 chain), one of the secreted proteins released from FB2, was significantly higher in the plasma of AD patients than in control patients, suggesting its potential use as a biomarker for AD diagnosis. Conclusions: Our work not only identified a pivotal role of a specific FB subtype in AD progression, but also shed light on cell interaction dynamics in vascular diseases.