mTOR signalling controls the formation of smooth muscle cell-derived luminal myofibroblasts during vasculitis.

IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2024-10-01 Epub Date: 2024-09-13 DOI:10.1038/s44319-024-00251-1
Angus T Stock, Sarah Parsons, Jacinta A Hansen, Damian B D'Silva, Graham Starkey, Aly Fayed, Xin Yi Lim, Rohit D'Costa, Claire L Gordon, Ian P Wicks
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Abstract

The accumulation of myofibroblasts within the intimal layer of inflamed blood vessels is a potentially catastrophic complication of vasculitis, which can lead to arterial stenosis and ischaemia. In this study, we have investigated how these luminal myofibroblasts develop during Kawasaki disease (KD), a paediatric vasculitis typically involving the coronary arteries. By performing lineage tracing studies in a murine model of KD, we reveal that luminal myofibroblasts develop independently of adventitial fibroblasts and endothelial cells, and instead derive from smooth muscle cells (SMCs). Notably, the emergence of SMC-derived luminal myofibroblasts-in both mice and patients with KD, Takayasu's arteritis and Giant Cell arteritis-coincided with activation of the mechanistic target of rapamycin (mTOR) signalling pathway. Moreover, SMC-specific deletion of mTOR signalling, or pharmacological inhibition, abrogated the emergence of luminal myofibroblasts. Thus, mTOR is an intrinsic and essential regulator of luminal myofibroblast formation that is activated in vasculitis patients and therapeutically tractable. These findings provide molecular insight into the pathogenesis of coronary artery stenosis and identify mTOR as a therapeutic target in vasculitis.

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mTOR 信号在脉管炎期间控制平滑肌细胞衍生的管腔肌成纤维细胞的形成。
肌成纤维细胞在发炎血管内膜层的聚集是脉管炎的一种潜在灾难性并发症,可导致动脉狭窄和缺血。在这项研究中,我们调查了川崎病(KD)期间这些管腔肌成纤维细胞是如何发育的,川崎病是一种典型的涉及冠状动脉的儿科血管炎。通过在 KD 小鼠模型中进行系谱追踪研究,我们发现管腔肌成纤维细胞的发育独立于临近壁成纤维细胞和内皮细胞,而是来源于平滑肌细胞(SMC)。值得注意的是,在小鼠和 KD、高安氏动脉炎和巨细胞动脉炎患者中,SMC 衍生的管腔肌成纤维细胞的出现与雷帕霉素机制靶标(mTOR)信号通路的激活相一致。此外,SMC特异性缺失 mTOR 信号或药物抑制可抑制管腔肌成纤维细胞的出现。因此,mTOR 是管腔肌成纤维细胞形成的内在重要调节因子,它在脉管炎患者中被激活,并且具有治疗作用。这些发现从分子角度揭示了冠状动脉狭窄的发病机制,并确定了 mTOR 是脉管炎的治疗靶点。
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来源期刊
EMBO Reports
EMBO Reports 生物-生化与分子生物学
CiteScore
11.20
自引率
1.30%
发文量
267
审稿时长
1 months
期刊介绍: EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry. 
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