TCF7 enhances pulmonary hypertension by boosting stressed natural killer cells and their interaction with pulmonary arterial smooth muscle cells.

IF 5.8 2区 医学 Q1 Medicine
Li-Wei Wu, Min Chen, Dai-Ji Jiang, Chen-Yu Jiang, Yi-Wei Liu, Bei Feng, Chen-Fei Shi, Xu Huang, Xu Zhang, Xiao-He Xu, Xing-Liang Zhou, Yi Shen, Tian-Yu Liu, Lin-Cai Ye, Yang-Yang He, Hao Zhang, Yi Yan
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引用次数: 0

Abstract

Background: Pulmonary hypertension (PH) is a life-threatening cardio-pulmonary disorder. Whether natural killer (NK) cells could act as participants in PH and the mechanism by which NK cells moderate pulmonary vascular remodeling has not been fully elucidated.

Methods: Single-cell RNA sequencing data from lungs of human pulmonary arterial hypertension (PAH) patients and monocrotaline (MCT)-induced PH rat model were retrieved from GEO database or UCSC Cell Browser. Tcf7 conditional knockout mice and TCF7 overexpression following adeno-associated virus 6 (AAV6) intratracheal delivery in rats were generated. The NK92 cell line and primary human pulmonary artery smooth muscle cells (hPASMCs) were used for in vitro experiments.

Results: Stressed NK cells were much higher in lungs from human PAH and MCT-induced PH compared to corresponding controls. Of note, TCF7 topped the list differentiating high-stressed from low-stressed human NK cells. TCF7-expressing NK cells displayed higher stress profile than TCF7-deficient cells. Tcf7-deficient NK cells exhibited lower Hsp90aa1 and Hsp90ab1 at transcriptional level and Hsp90 at protein level than Tcf7-expressing cells 24 h post-hypoxia. Mechanistically, TCF7-overexpressing NK cells secrete more SPP1 compared to control NK cells, thus promoting the proliferation and migration of hPASMCs 48 h post-hypoxia. TCF7 overexpression in rats aggravated PH features, while Tcf7 deficiency in mice alleviated pulmonary remodeling possibly due to the manipulation of HSP90 level in NK cells and SPP1 in the microenvironment.

Conclusions: TCF7 contributes to the immunopathology of PH possibly through upregulation of stressed NK cells. Under stress conditions, NK cells promote the proliferation and migration of hPASMC through paracrine effects, thereby further promoting vascular remodeling.

TCF7通过促进应激自然杀伤细胞及其与肺动脉平滑肌细胞的相互作用来增强肺动脉高压。
背景:肺动脉高压(PH)是一种危及生命的心肺疾病。自然杀伤细胞(natural killer, NK)是否在PH中起参与者作用,以及NK细胞调节肺血管重构的机制尚未完全阐明。方法:从GEO数据库或UCSC Cell Browser中检索人肺动脉高压(PAH)患者和MCT诱导的PH大鼠肺单细胞RNA测序数据。实验产生了Tcf7条件敲除小鼠和腺相关病毒6 (AAV6)气管内给药后Tcf7过表达小鼠。采用NK92细胞系和原代人肺动脉平滑肌细胞(hPASMCs)进行体外实验。结果:与相应的对照组相比,PAH和mct诱导的PH在肺部的应激NK细胞要高得多。值得注意的是,TCF7在区分高应激和低应激人类NK细胞方面名列榜首。表达tcf7的NK细胞比缺乏tcf7的细胞表现出更高的应激谱。缺氧24小时后,tcf7缺失NK细胞的Hsp90aa1和Hsp90ab1转录水平和Hsp90蛋白水平均低于表达tcf7的细胞。在机制上,与对照NK细胞相比,过表达tcf7的NK细胞分泌更多的SPP1,从而促进缺氧后48 h hPASMCs的增殖和迁移。大鼠中TCF7过表达加重了PH特征,小鼠中TCF7缺乏减轻了肺重构,可能与NK细胞中HSP90水平和微环境中SPP1水平的改变有关。结论:TCF7可能通过上调应激NK细胞参与PH的免疫病理。在应激条件下,NK细胞通过旁分泌作用促进hPASMC的增殖和迁移,从而进一步促进血管重构。
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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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