Wu Li-Wei, Chen Min, Jiang Dai-Ji, Jiang Chen-Yu, Liu Yi-Wei, Feng Bei, Shi Chen-Fei, Huang Xu, Zhang Xu, Xu Xiao-He, Zhou Xing-Liang, Shen Yi, Liu Tian-Yu, Ye Lin-Cai, He Yang-Yang, Zhang Hao, Yan Yi
Heart Center and Shanghai Institute of Pediatric Congenital Heart Disease, Shanghai Children's Medical Center, National Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Clinical Research Center for Rare Pediatric Diseases, Shanghai Children's Medical Center, National Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Respir Res. 2025 May 29;26(1):202. doi: 10.1186/s12931-025-03276-9.
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.
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.
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.
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.
肺动脉高压（PH）是一种危及生命的心肺疾病。自然杀伤（NK）细胞是否可作为PH的参与者，以及NK细胞调节肺血管重塑的机制尚未完全阐明。
从基因表达综合数据库（GEO数据库）或加州大学圣克鲁兹分校细胞浏览器中检索人类肺动脉高压（PAH）患者肺部以及野百合碱（MCT）诱导的PH大鼠模型的单细胞RNA测序数据。构建Tcf7条件性敲除小鼠，并通过腺相关病毒6（AAV6）气管内注射使大鼠过表达TCF7。使用NK92细胞系和原代人肺动脉平滑肌细胞（hPASMCs）进行体外实验。
与相应对照组相比，人类PAH和MCT诱导的PH患者肺部的应激NK细胞数量明显更多。值得注意的是，在区分高应激和低应激人类NK细胞方面，TCF7位居榜首。表达TCF7的NK细胞比缺乏TCF7的细胞表现出更高的应激特征。缺氧24小时后，缺乏Tcf7的NK细胞在转录水平上的Hsp90aa1和Hsp90ab1以及蛋白质水平上的Hsp90均低于表达Tcf7的细胞。从机制上讲，与对照NK细胞相比，过表达TCF7的NK细胞分泌更多的SPP1，从而在缺氧48小时后促进hPASMCs的增殖和迁移。大鼠中TCF7的过表达加剧了PH特征，而小鼠中Tcf7的缺乏减轻了肺重塑，这可能是由于对NK细胞中HSP90水平和微环境中SPP1的调控所致。
TCF7可能通过上调应激NK细胞而促进PH的免疫病理学发展。在应激条件下，NK细胞通过旁分泌作用促进hPASMCs的增殖和迁移，从而进一步促进血管重塑。
